Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:12]=1[C:13]([NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:14].[O:28]1CCOC[CH2:29]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:11]2[C:12](=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:13](=[O:14])[N:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:29]1=[O:28]
Reactant: CCOC(=O)CNC(=O)c1cc(OC)ccc1NCc1ccc(Cl)cc1Cl
Reactant: C1COCCO1
Product: CCOC(=O)Cn1c(=O)c2cc(OC)ccc2n(Cc2ccc(Cl)cc2Cl)c1=O
Temperature: 140 °C

Procedure:
Into 10 ml of dioxane were dissolved 5.2 g of ethyl (2-((2,4-dichlorophenyl)methyl)amino-5-methoxybenzoyl)aminoacetate and 6.2 g of N,N'-carbonyldiimidazole, and the solution was heated to 140° to 150° C. After distilled off dioxane, the mixture was further heated for 15 minutes at 140° C. After cooling, ethanol was added and the crystalline substances were collected by filtration. They were recrystallized from ethanol to obtain 2,8 g of title compound. m.p. 167°-168° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[C:6](O)=[N:5]2.P(Cl)(Cl)([Cl:18])=O.C(N(CCC)CCC)CC>>[Cl:18][C:6]1[C:7]2[N:8]([CH:12]=[N:13][N:14]=2)[C:9]2[C:4]([N:5]=1)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc2cc(F)ccc2n2cnnc12
Agent: CCCN(CCC)CCC
Product: Fc1ccc2c(c1)nc(Cl)c1nncn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame-dried reaction flask under a dry nitrogen atmosphere, there were placed 8.9 g. (0.044 mole) of 7-fluoro-4-hydroxy-[1,2,4]triazolo[4,3-a]quinoxaline and 160 ml. of phosphorus oxychloride together with 8.9 ml. of tri-n-propylamine. The reaction mixture was then refluxed overnight for approximately 16 hours and finally cooled to room temperature before being poured over ice/water with mechanical stirring. The resulting aqueous mixture was then stirred at room temperature for 30 minutes and filtered, and the solid product so obtained was subsequently washed with cold water and triturated with ethyl acetate to ultimately afford 7.0 g.(71%) of pure 4-chloro-7-fluoro-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 305°-308° C. Mass Spectrum: m/e, 222 (P); m/e, 224 (P+2).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]([NH2:12])=[O:11].CN(C1C=CC=CN=1)C.[C:22](Cl)(=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:25][CH:24]([CH3:26])[CH2:23][C:22]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH:7]([CH3:8])[CH3:9])[C:3]=1[C:10]([NH2:12])=[O:11])=[O:27]
Reactant: CC(C)CC(=O)Cl
Reactant: CC(C)c1noc(N)c1C(N)=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)CC(=O)Nc1onc(C(C)C)c1C(N)=O
Reaction time: 16 h

Procedure:
1.7 g of 5-amino-3-isopropylisoxazole-4-carboxamide in a mixture of 40 ml of toluene and 40 ml of pyridine are initially taken together with a pinch of dimethylaminopyridine, and a solution of 2.5 g of isovaleroyl chloride in 20 ml of toluene is added. Stirring is carried out for 16 hours at room temperature, after which the solution is evaporated to dryness and the residue is stirred with ethyl acetate. The organic phase is then extracted with aqueous hydrochloric acid and sodium bicarbonate solution, dried and evaporated down. Purification is effected by chromatography over silica gel (cyclohexane/ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:8]=[O:9]>>[OH:9][CH2:8][CH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: C=O
Reactant: Cc1cnccn1
Product: OCCc1cnccn1
Yield: 31.5 %

Procedure:
A mixture of 90.0 g (956 mmol) of 2-methylpyrazine and 6.4 g (212 mmol) of paraformaldehyde was heated in a stainless steel autoclave at 165° C. for 5 hours, The residue was distilled under iced aspirator pressure (ca. 10 mmHg) to yield 8.28 g (32%) of a light pink oil.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[C:27]([CH3:35])[CH:26]=3)[CH:19]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[C:27]([CH3:35])[CH:26]=3)[CH:19]=2)[OH:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Nc2cccc(C(=O)CCN3CCC(Cc4ccccc4)CC3)c2)c2ccccc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2cccc(C(O)CCN3CCC(Cc4ccccc4)CC3)c2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
To a solution of Example 209 (0.15 g, 0.32 mmol) in THF (5.0 ml) was added LAH (1.0 M in THF, 0.66 ml, 0.66 mmol) at 0° C. The mixture was stirred at room temperature overnight before it was quenched with Na2SO4.10H2O (pellets) until no further bubbles was observed. The mixture was diluted with ethyl acetate and the solids filtered. The filterate was washed with water (50 ml), brine (50 ml), dried over MgSO4 and concentrated on a rotovap to give the desired alcohol as a yellow solid (0.04 g, 27%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[NH:5][CH:4]([O:14][CH:15]([CH3:17])[CH3:16])[CH2:3]1.I[C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1>C(NCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([O:14][CH:15]([CH3:16])[CH3:17])[CH2:3]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)NC(OC(C)C)CC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)N=C(OC(C)C)CC3(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.097 g (0.40 mmol) of 4,4-dimethyl-2-isopropoxy-1,2,3,4-tetrahydro-7-ethynylquinoline (Compound 27) and 1.16 g (0.75 ml, 4.2 mmol) of ethyl 4-iodobenzoate in 3.0 ml of diethylamine which was degassed under argon for 15 min, was added 0.043 g (0.23 mmol) of copper(I) iodide and then 0.064 g (0.09 mmol) of bis(triphenylphosphine)palladium(II) chloride. The reaction was stirred at room temperature for 16 h. The reaction mixture was then concentrated. Purification by flash chromatography (1.5% EtOAc in hexane) gave the title compound as an oil. PNMR (CDCl3) d 8.00 (2H, d, J=8.2 Hz), 7.54 (2H, d, J=8.1 Hz), 7.32 (1H, s), 7.23 (2H, s), 5.40 (1H, p, J=6.3 Hz), 4.37 (2H, q, J=7.1 Hz), 2.24 (2H, s), 1.39 (3H, t, J=7.1 Hz), 1.32 (6H, d, J=6.2 Hz), 1.24 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[SH:34][C:35]1[N:39]([CH3:40])[N:38]=[N:37][N:36]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:34][C:35]2[N:39]([CH3:40])[N:38]=[N:37][N:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nnnc1S
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1nnnc1SC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) in dry THF (30 mL) were added triphenylphosphine (2.0 g, 7.5 mmol) and 5-mercapto-1-methyl-1H-tetrazole (0.70 g, 6.0 mmol). To the mixture was added diisopropyl azodicarboxylate (1.2 mL, 6.0 mmol) under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL), which was washed with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, successively. The solvent was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (50 g, diethyl ether-hexane 1:1) to give the titled compound as a colorless oily substance. (1.11 g, 74%).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([N+]([O-])=O)=[CH:9][C:8]=1[CH3:16])[CH2:3][C:4]([OH:6])=[O:5].CC1C=C([N+:26]([O-:28])=[O:27])C=CC=1C=O.C(O)(=O)CC(O)=O.C([O-])(=O)C.[NH4+]>C(O)C>[NH2:1][CH:2]([C:7]1[CH:12]=[C:11]([N+:26]([O-:28])=[O:27])[CH:10]=[CH:9][C:8]=1[CH3:16])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: Cc1cc([N+](=O)[O-])ccc1C=O
Reactant: Cc1cc([N+](=O)[O-])ccc1C(N)CC(=O)O
Agent: CC(=O)[O-]
Agent: O=C(O)CC(=O)O
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])cc1C(N)CC(=O)O
Yield: 45 %

Procedure:
Following the General Procedure of Description 3, 3-amino-3-(2-methyl-4-nitro-phenyl)propanoic acid (2c) was prepared from 2-methyl-4-nitro-benzaldehyde (2b) (800 mg, 5.0 mmol), malonic acid (520 mg, 5.0 mmol), and ammonium acetate (NH4OAc) (578 mg, 7.5 mmol) in ethanol (EtOH) (10 mL) at reflux for 48 h (oil bath). The reaction was followed by LC/MS to completion. Filtrative work-up afforded 510 mg (45% yield) of the target compound (1c) as a near colorless solid which was of sufficient purity to be used directly in the next step without further purification and isolation. 1H NMR (300 MHz, D2O): δ 8.01-7.97 (m, 2H), 7.46 (d, J=8.4 Hz, 1H), 4.83 (t, J=7.2 Hz, 1H), 2.70-2.65 (m, 2H), 2.33 (s, 3H) ppm. LC/MS: Rt=1.274 min; ESI (pos.) m/z=225.1 (M+H+)+.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([CH:16]1[CH2:21][CH2:20][O:19][CH2:18][C:17]1=O)[CH2:12][CH2:13][CH:14]=[CH2:15]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]=[C:17]1[CH:16]([CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])[CH2:21][CH2:20][O:19][CH2:18]1
Reactant: C=CCCCC1CCOCC1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCC1CCOCC1=C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NaHMDS (5.35 ml, 10.70 mmol) was added to methyltriphenylphosphonium bromide (3822 mg, 10.70 mmol) in THF (53.500 ml) at RT. The reaction was stirred at RT for 1 hr before 4-(pent-4-en-1-yl)dihydro-2H-pyran-3(4H)-one (900 mg, 5.35 mmol) in THF (2 mL) was added at 0° C. The reaction mixture was stirred at room temperature for 2 hr. The mixture was cooled and quenched with aqueous NH4Cl. The reaction mixture was extracted with diethyl ether (3×20 mL). The combined organic fractions were washed with water and brine (saturated, 100 mL), dried, filtered and the solvent was evaporated under reduced pressure (400 mmhg). The residue was purified by column chromatography on silica gel to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 5.75-5.89 (m, 1H), 4.92-5.06 (m, 2H), 4.86 (s, 1H), 4.77 (t, 1H, J=1.5 Hz), 4.12 (d, 1H, J=12.1 Hz), 3.86-3.96 (m, 2H), 3.57-3.65 (m, 1H), 2.15-2.24 (m, 1H), 2.00-2.12 (m, 2H), 1.81-1.91 (m, 1H), 1.64-1.76 (m, 1H), 1.21-1.52 (m, 4H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[S:11])([OH:3])=[O:2].[CH2:12]([N:14]([CH2:23][CH3:24])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[CH3:13].O>CN(C)C=O>[C:1]([CH2:4][N:5]1[C:9](=[O:10])[C:8](=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([N:14]([CH2:12][CH3:13])[CH2:23][CH3:24])=[CH:16][CH:17]=2)[S:7][C:6]1=[S:11])([OH:3])=[O:2]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: O=C(O)CN1C(=O)CSC1=S
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(C=C2SC(=S)N(CC(=O)O)C2=O)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
In 30 ml of dimethylformamide were dissolved 3.82 g of 3-carboxymethylrhodanine and 3.54 g of p-diethylaminobenzaldehyde, and the solution was stirred at 100° C. for 3 hours. After termination of the reaction, the solution was poured into water, and the formed precipitate was recovered by filtration, washed with water and recrystallized from acetone to obtain 3-carboxymethyl-5-(p-diethylaminobenzylidene)rhodanine (the yield was 87%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1.Cl.NCC1C=CC(CC(O)=O)=CC=1.[C:27]([O:31][C:32](ON=C(C1C=CC=CC=1)C#N)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCc1cccc(CC(=O)O)c1
Agent: Cl
Agent: NCc1ccc(CC(=O)O)cc1
Product: CC(C)(C)OC(=O)NCc1cccc(CC(=O)O)c1

Procedure:
Substitution of an equivalent amount of 3-aminomethylphenylacetic acid hydrochloride for 4-aminomethylphenylacetic acid hydrochloride in the reaction with 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile described in Example 54 gave 3-(N-t-butoxycarbonylaminomethyl)phenylacetic acid, m.p. 95°-96.5°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C@H:7]1[N:25]([CH3:26])[C:24](=[O:27])[C@H:23]([CH2:28][CH2:29][CH2:30][NH:31]C(=O)OCC2C=CC=CC=2)[NH:22][C:21](=[O:42])[C@@H:20]([NH:43]C(OCC2C=CC=CC=2)=O)[CH2:19][C:18]2[CH:54]=[C:14]([CH:15]=[CH:16][C:17]=2[O:55]CC2C=CC=CC=2)[C:13]2=[CH:63][C:9](=[C:10]([F:64])[CH:11]=[CH:12]2)[CH2:8]1)=[O:6]>[Pd].C(O)(=O)C.O.C(O)C>[NH2:43][C@H:20]1[CH2:19][C:18]2[CH:54]=[C:14]([CH:15]=[CH:16][C:17]=2[OH:55])[C:13]2=[CH:63][C:9](=[C:10]([F:64])[CH:11]=[CH:12]2)[CH2:8][C@@H:7]([C:5]([NH:4][CH2:3][CH2:2][NH2:1])=[O:6])[N:25]([CH3:26])[C:24](=[O:27])[C@H:23]([CH2:28][CH2:29][CH2:30][NH2:31])[NH:22][C:21]1=[O:42]
Reactant: CN1C(=O)[C@H](CCCNC(=O)OCc2ccccc2)NC(=O)[C@@H](NC(=O)OCc2ccccc2)Cc2cc(ccc2OCc2ccccc2)-c2ccc(F)c(c2)C[C@H]1C(=O)NCCN
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=O)[C@H](CCCN)NC(=O)[C@@H](N)Cc2cc(ccc2O)-c2ccc(F)c(c2)C[C@H]1C(=O)NCCN
Reaction time: 15 h

Procedure:
25 mg (0.029 mmol) of benzyl {3-[(8S,11S,14S)-8-{[(2-aminoethyl)amino]carbonyl}-17-(benzyloxy)-14-{[(benzyloxy)carbonyl]-amino}-5-fluoro-9-methyl-10,13-dioxo-9,12-diazatricyclo[14.3.1.12,6]henicosa-1(20),2(21),3,5,16,18-hexaen-11-yl]pro-pyl}carbamate (Example 30O) are added into a mixture of 5 ml of acetic acid/water/ethanol (4:1:1) mixture. 10 mg of palladium on activated carbon (10%) are added, and the mixture is hydrogenated under atmospheric pressure at RT for 15 h. The reaction mixture is filtered through prewashed kieselguhr, washed with ethanol, and the filtrate is concentrated in vacuo on a rotary evaporator. The residue is mixed with 0.1N hydrochloric acid and concentrated in vacuo. The remaining solid is dried under high vacuum. The trihydrochloride is converted into the tri(hydrotrifluoroacetate) by preparative HPLC (Kromasil 100C18, mobile phase acetonitrile/0.2% aqueous trifluoroacetic acid 5:95→95:5).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8][N:7]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[C:11]([C:9]1[NH:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)c1cc(C(C)(C)C)[nH]n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(C(=O)O)n[nH]1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 87.4 %

Procedure:
5-tert-Butyl-1H-pyrazol-3-carboxylic acid ethyl ester (20 g, 100 mmol) and 1M NaOH solution (250 ml, 250 mmol) were dissolved in 1,4-dioxan (300 ml), the reaction was heated to 60° C. under nitrogen and stirred for 2.5 hours. The reaction was then cooled to room temperature and stirred for a further 18 hours. The reaction mixture was adjusted to pH 2 using concentrated hydrochloric acid, extracted with ethyl acetate (4×200 ml) and the combined organic extracts washed with brine (100 ml). The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to give 5-tert-butyl-1H-pyrazol-3-carboxylic acid (14.7 g) as a pale yellow solid. 1H NMR (400 MHz, DMSO-D6): δ=12.80-12.88 (2H, brs), 6.41 (1H, s), 1.11 (9H, s) ppm. LRMS (electrospray): m/z [M+H]+ 169, [M+Na]+ 191, [M−H]+ 167.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:15][CH2:16]Cl)[S:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:7])=[O:6].[H-].[Na+]>CN(C=O)C>[Cl:1][CH2:2][CH2:3][N:4]1[CH2:15][CH2:16][N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:5]1(=[O:7])=[O:6]
Reactant: O=S(=O)(Nc1ccccc1)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)N(CCCl)CCN1c1ccccc1
Reaction time: 12 h

Procedure:
Using a slow dropper, a solution of 12.6 g of the product obtained in Step 2 above in 25 ml of DMF is introduced onto a suspension of 1.4 g of NaH in 175 ml of DMF and stirring is carried out for 12 hours. The reaction mixture is then poured onto ice in order to bring about crystallisation of the expected product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:13][C:14]2[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[C:9]([F:12])([F:11])[F:10])=[CH:4][N+:3]=1[O-].O.C(=O)([O-])[O-:34].[K+].[K+]>C(OC(=O)C)(=O)C>[F:10][C:9]([F:12])([F:11])[CH:8]([C:5]1[CH:4]=[N:3][C:2]([CH2:1][OH:34])=[CH:7][CH:6]=1)[O:13][C:14]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[N:22][C:21]2[C:16]([N:15]=1)=[CH:17][CH:18]=[CH:19][CH:20]=2
Reactant: O=C([O-])[O-]
Reactant: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(c1ccc(C)[n+]([O-])c1)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(c1ccc(CO)nc1)C(F)(F)F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 29.9 %

Procedure:
Compound B2 (103 mg, 0.226 mmol) obtained in Step 2 was suspended in acetic anhydride (1.0 mL) and the suspension was stirred at 100° C. for 1.5 hours. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in methanol (2.0 mL). Potassium carbonate (93.7 mg, 0.678 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and a saturated aqueous ammonium chloride solution and water were added. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) and further purified by preparative thin-layer chromatography (hexane/ethyl acetate=1/1) to give Compound 31 (30.8 mg, 30% yield).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([Br:7])[N:6]=1.S(Cl)(Cl)=O.C1(C)C=CC=CC=1.[OH-].[NH4+:23].O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[S:3][C:4]([C:8]([NH2:23])=[O:10])=[C:5]([Br:7])[N:6]=1
Reactant: O=C(O)c1sc(Br)nc1Br
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: NC(=O)c1sc(Br)nc1Br
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69 %

Procedure:
A suspension of 2,4-dibromo-1,3-thiazole-5-carboxylic acid (16.33 g, 56.91 mmol) in dry DCM (250 mL) and DMF (0.400 mL) was cooled with ice bath. Thionyl chloride (40.0 mL, 548 mmol) was added dropwise. The cooling bath was removed and the suspension was stirred at r.t. for 2.5 hours, Toluene (80 mL, 800 mmol) was added and the suspension was heated to reflux for 1 hour. The mixture was cooled to room temperature, solvent was removed and the residue was azeotroped with toluene (2×100 mL) to give a crude intermediate. This material was suspended in DCM (230 mL) and cooled with ice bath. N,N-dimethylaminopyridine (0.70 g, 5.7 mmol) was added, followed by slow addition of 8.5 M of Ammonium hydroxide in Water (100.0 mL, 850.0 mmol). The mixture was stirred at room temperature overnight. The mixture was filtered, aqueous layer was separated and extracted with DCM (3×100 mL). The combined DCM layers were washed with water, brine, dried over Na2SO4, filtered, and evaporated to give a solid product (11.2 g, 69%). LCMS: (FA) ES+ 287 and ES− 285.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=4[F:28])=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH3:29][C@@H:30]1[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[NH:31]1>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:31]5[C@H:30]([CH3:29])[CH2:34][CH2:33][S:32]5(=[O:36])=[O:35])=[CH:23][C:22]=4[F:28])=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(I)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Product: C[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)c(F)c1
Yield: 42.2 %

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](2-fluoro-4-iodophenyl)methanone (491 mg) described in Preparation Example 164 and (R)-3-methylisothiazolidine 1,1-dioxide (135 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (210 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5](O)=[O:6].[CH2:12]([N:14](CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([NH:14][CH3:12])=[O:6]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(Br)cc(I)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Br)cc(I)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
37.5 g (115 mmol) of 3-bromo-5-iodobenzoic acid in 300 ml of dimethylformamide are introduced into a round-bottomed flask under a stream of nitrogen. 17.6 ml (127 mmol) of triethylamine, 17 g (126 mmol) of 1-hydroxybenzotriazole and 7.75 g (115 mmol) of methylamine hydrochloride are added. The reaction medium is cooled to 0° C., followed by portionwise addition of 24.2 g (126 mmol) of 1-[3-(dimethyl-amino)propyl]-3-ethylcarbodiimide hydrochloride. The medium is allowed to warm to room temperature and is stirred for 18 hours. It is then poured into water and the precipitate obtained is filtered off, washed with heptane and then dried. 37.3 g (96%) of the expected product are obtained in the form of a beige-colored powder with a melting point of 205° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[OH:26][C:20]1([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:25][CH2:24][CH2:23][N:22]([C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:8])[CH2:21]1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc(C#N)cc3)C2)c1

Procedure:
The compound of Example 12 was prepared according to the general preparation protocol A from 4-cyanobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:17][C:18]1[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=1.C(Cl)Cl>C(O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:2]2[NH:1][C:19]3[N:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]=2[CH:12]=1
Reactant: Nc1cccnc1Cl
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: Clc1ccc2c(c1)C(c1ccccc1)=Nc1cccnc1N2
Temperature: 200 °C
Reaction time: 1 h
Yield: 15.2 %

Procedure:
A mixture of 15.0 g (0.0647 mole) of 2-amino-5-chlorobenzophenone and 9.1 g (0.068 mole) of 3-amino-2-chloropyridine was heated at 200° C. (in an oil bath) for 0.75 hr under nitrogen atmosphere. The mixture was cooled and methylene chloride added. The mixture was stirred for 1 hr then allowed to stand overnight. Brown solid precipitate weighing 8.7 g was separated by filtration. The filtrate was evaporated under reduced pressure. The residue was combined with the brown solid and partitioned with aqueous sodium hydroxide and methylene chloride and crude product isolated as in Example 1, except the crystallizing solvent was ethanol. Recrystallization from ethanol and drying over night at 82° C./0.1 mm Hg gave 3.0 g product; m.p. 156.5°-158.5° C.