Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([C:6]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][CH3:18])[CH2:12][CH2:11][C:10]=2[CH:9]=[N:8][C:7]=1[OH:19])=O)C.[ClH:20]>>[ClH:20].[ClH:20].[OH:19][C:7]1[N:8]=[CH:9][C:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][C:16]=2[CH:6]=1
Reactant: CCOC(=O)c1c(O)ncc2c1CCN(CC)CC2
Agent: Cl
Product: CCN1CCc2cnc(O)cc2CC1

Procedure:
Prepared from 4-ethoxycarbonyl-3-hydroxy-7-ethyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepine by treatment with hydrochloric acid at 130° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([OH:7])[C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:25][C:19]([O:7][C:4]1[C:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[C:2]([CH3:1])[NH:6][N:5]=1)([CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Cc1[nH]nc(O)c1-c1cccc2ccccc12
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1n[nH]c(C)c1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-methyl-4-(naphthalen-1-yl)-1H-pyrazol-3-ol (200 mg, 0.89 mmol), ethyl bromoisobutyrate (0.14 mL, 0.89 mmol) and potassium carbonate (136 mg, 0.98 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. Water was then added to the reaction mixture, extracted with ethyl acetate, dried over sodium sulfate and concentrated. Purification by preparative thin layer chromatography (95% dichloromethane/5% methanol) afforded compound ethyl 2-methyl-2-(5-methyl-4-(naphthalen-1-yl)-1H-pyrazol-3-yloxy)propanoate as a solid.
Reaction SMILES: [C:1]([C:3]1([C:9](OC)=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:2][CH2:1][C:3]1([CH2:9][OH:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1(C#N)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(CO)CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the crude product from step 1 (0.944 g, 5.58 mmol) in THF (5 ml) (a dark brown solution) at 0° C. was added LAH (5.58 ml, 5.58 mmol) dropwise via a syringe. The brown mixture was warmed to room temperature and stirred for 18 hours. The resulting mixture was yellow cloudy. LC/MS showed containing desired product. To the reaction was added sodium sulfate decahydrate solid at 0° C. The mixture was stirred at room temperature for 20 min., then filtered and washed with DCM. The yellow filtrate was concentrated in vacuo to give 0.74 g of orange oil. This crude material was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[S:33][C:32]([C:34]2([C:44]#[N:45])[CH2:43][CH2:42][C:37]3([O:41][CH2:40][CH2:39][O:38]3)[CH2:36][CH2:35]2)=[N:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([C:29]2[S:33][C:32]([C:34]3([C:44]#[N:45])[CH2:43][CH2:42][C:37]4([O:41][CH2:40][CH2:39][O:38]4)[CH2:36][CH2:35]3)=[N:31][CH:30]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: N#CC1(c2ncc(Br)s2)CCC2(CC1)OCCO2
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C#N)CCC4(CC3)OCCO4)s2)c1
Temperature: 100 °C
Yield: 79.4 %

Procedure:
N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (1.60 g, 4.22 mmol), 8-(5-bromo-1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (1.40 g, 4.22 mmol), cesium carbonate (4.12 g, 12.6 mmol), Pd2(dba)3 (193 mg, 0.21 mmol) and X-Phos (201 mg, 0.42 mmol) were added to a flame-dried flask, deoxygenated, and diluted with anhydrous 1,4-dioxane (15 ml) and water (1.5 ml). The resulting dark mixture was heated to 100° C. for 5 h. The reaction mixture was diluted with 1:1 saturated aqueous NaHCO3: brine (100 ml) and extracted with EtOAc (2×85 ml). The organic layers were dried over Na2SO4, filtered and concentrated. The crude dark maroon oil was purified via flash column chromatography (SiO2: 100% Hex to 60:40 Hex:EtOAc) which afforded 8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]decane-8-carbonitrile (1.77 g, 3.35 mmol, 79% yield) as an off-white solid. MS ESI: [M+H]+ m/z 502.1. 1H NMR (500 MHz, CD3OD): δ 11.1 (s, 1H), 9.65 (d, 1H, J=4.9 Hz), 8.93 (s, 1H), 8.83 (s, 1H), 8.30 (s, 1H), 8.10 (d, 1H, J=4.9 Hz), 8.02 (s, 1H), 4.73-4.72 (m, 4H), 3.21-3.18 (m, 2H), 3.13 (s, 3H), 3.01-2.97 (m, 2H), 2.69-2.61 (m, 4H). rhSYK activity=+++
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.C(Cl)(Cl)Cl>[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][CH2:6][C:7]([NH:59][C:56]1[S:57][C:58]2[C:50]([CH:45]3[CH2:46][O:47][CH2:48][CH2:49][O:44]3)=[CH:51][CH:52]=[C:53]([O:60][CH3:61])[C:54]=2[N:55]=1)=[O:8]
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: CN(C)CCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)CCCN(C)C)nc12

Procedure:
From 4-(dimethylamino)butyric acid hydrochloride, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+24.2° (c=0.53, CHCl3), ES-MS m/e (%): 380 (M+H+, 100).
Reaction SMILES: [BH4-].[Na+].C(O)(C(F)(F)F)=O.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:24]#[N:25])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH2:24][NH2:25])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C#N)c2ccccc2Cl)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.6 %

Procedure:
To NaBH4 (0.79 g, 20.84 mmol) in THF (20 mL) at 0° C. was added TFA (2.38 g, 20.84 mmol) dropwise. To this cooled mixture was added 4-[(2-Chloro-phenyl)-cyano-methyl)-piperazine-1-carboxylic acid tert-butyl ester (101) (1.40 g, 4.17 mmol) in THF (10 mL) dropwise. The reaction mixture was allowed to stir at room temperature for 18 h. The reaction was quenched with H2O (50 mL) and diluted with EtOAc (100 mL). The organic phase was washed with H2O (100 mL) and brine (100 mL). The crude material was purified by chromatography (silica gel 60 mesh, eluting with 10% TEA/10% MeOH in EtOAc) yielding 0.49 g (34%) pure product.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]([CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)[C:12](OCC)=[O:13])C>C(OCC)C>[CH2:26]([O:25][CH2:24][C:11]([C:17]1[CH:18]=[CH:19][C:20]([Br:23])=[CH:21][CH:22]=1)([CH2:10][OH:9])[CH2:12][OH:13])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(COCc1ccccc1)(C(=O)OCC)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(CO)(COCc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 35.7 %

Procedure:
To a 0° C. suspension of LAH (444 mg, 11.1 mmol) in diethyl ether (10 mL) was added a solution of 2-Benzyloxymethyl-2-(4-bromo-phenyl)-malonic acid diethyl ester (1.67 g, 3.84 mmol) in diethyl ether (10 mL) dropwise via addition funnel. The reaction mixture was warmed to room temperature and stirred for 22 hours. The reaction was quenched with water (1.5 mL), 15% NaOH (1.5 mL), and water (3 mL) added sequentially. The white slurry was stirred for 30 minutes, diluted with ethyl acetate and filtered to remove the aluminum salts. The filtrate was concentrated in vacuo to afford a green semisolid, which was purified by flash chromatography (40 g silica, 30-82% ethyl acetate/heptane, 10 column volumes). Product fractions were combined and concentrated in vacuo to afford the title compound as a colorless oil (482 mg, 36% yield). 1H NMR (500 MHz, CD3OD) δ ppm 7.45 (d, J=8.54 Hz, 2 H), 7.35 (d, J=8.78 Hz, 2 H), 7.22-7.33 (m, 5 H), 4.51 (s, 2 H), 3.92 (s, 4 H), 3.82 (s, 2 H).
Reaction SMILES: C(N(CC)CC)C.[Cl-].[CH:9]1([CH2:15][C:16]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]3)[S:21][CH:22]=2)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([N:37]=[C:38]=[O:39])[CH:31]=1.N12CCCN=C1CCCCC2>ClCCl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([NH:37][C:38]([N:26]2[CH2:25][CH2:24][CH:23]([C:20]3[S:21][CH:22]=[C:18]([C:16](=[O:17])[CH2:15][CH:9]4[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]4)[N:19]=3)[CH2:28][CH2:27]2)=[O:39])[CH:31]=1
Reactant: O=C(CC1CCCCC1)c1csc(C2CC[NH2+]CC2)n1
Reactant: Cc1ccc(Cl)cc1N=C=O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(Cl)cc1NC(=O)N1CCC(c2nc(C(=O)CC3CCCCC3)cs2)CC1
Reaction time: 0.08 h
Yield: 91.5 %

Procedure:
Triethylamine (0.047 ml) was added to a mixture of 4-[4-(cyclohexylacetyl)-1,3-thiazol-2-yl]piperidinium chloride (100 mg) in dichloromethane (1 ml). After the solid had dissolved completely, 4-chloro-2-isocyanato-1-methylbenzene (51 mg) and a drop of 1,8-diazabicyclo[5.4.0]undec-7-ene were added. The reaction mixture was then stirred for 5 minutes. Solvent and triethylamine were removed under reduced pressure. Purification of the residue by column chromatography gave N-(5-chloro-2-methylphenyl)-4-[4-(cyclohexylacetyl)-1,3-thiazol-2-yl]piperidine-1-carboxamide (128 mg).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:9]([CH2:11][NH2:12])[OH:10].C(N(CC)CC)C>ClCCl>[Si:1]([O:10][CH2:9][CH2:11][NH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyldimethylsilylchloride (24.87 g, 165 mmol) was added portion wise to a solution of ethanolamine (11.84 mL, 150 mmol) in triethylamine (46.0 mL, 330 mmol) and dichloromethane (100 mL) at 0° C. The reaction was stirred at this temperature for 1 hour and then allowed to warm to room temperature. After 16 hours, the reaction mixture was washed with sodium hydrogen carbonate solution (2×50 mL) and brine (50 mL), dried over magnesium sulfate, and concentrated in vacuo to give 2-(tert-butyldimethylsilyloxy)ethylamine as a colourless oil. Yield: 24.1 g, 137 mmol, 92%. 1H NMR (400 MHz, CDCl3) δ: 3.63 (2H, t), 2.78 (2H, t), 0.91 (9H, t), 0.07 (6H, s).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[C:18]([NH:28][C:29](=[O:37])[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:17]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:29]([NH:28][C:18]2[N:17]=[C:16]([NH:15][C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]3[NH2:8])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=2)=[O:37])=[CH:35][CH:34]=1
Reactant: COc1ccc2nc(NC(=O)c3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2nc(NC(=O)c3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3N)c2c1
Yield: 82.3 %

Procedure:
A solution of 120 mg of cis-N-tert-butoxycarbonyl-2-[2-(4-chlorobenzoylamino)-6-methoxyquinazolin-4-yl]aminocyclohexylamine in 5 mL of methylene chloride was combined with 2 mL of trifluoroacetic acid, and reacted at room temperature for 1 hour. The reaction solution was basified by addition of a saturated solution of sodium hydrogen carbonate, extracted with chloroform, and dried. After the solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform:methanol=30:1) to obtain 80 mg of the desirable compound.
Reaction SMILES: C1C=CC=CC=1.[C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH3:8].[CH2:16](O)[CH2:17][OH:18]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:16]1[CH2:17][O:18][C:7]([CH3:8])([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:9]1
Reactant: CCOC(=O)CC(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CC1(C)OCCO1
Yield: 92 %

Procedure:
Benzene (50 cc), ethyl acetylacetate (30 g, 231 mmol) and ethylene glycol (16 g), followed by p-toluenesulphonic acid (0.5 g), are introduced into a round-bottomed flask fitted with a Dean and Stark apparatus. The mixture is heated under reflux while the azeotrope is distilled off for 2 hours 30 minutes. After the removal of benzene, ethyl 3,3-ethylenedioxybutanoate (37 g) is obtained (B.P.12 =98° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1.C(COC)OC.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:9]1[CH:14]=[C:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1cccc(-c2ccccn2)c1
Yield: 75 %

Procedure:
A mixture of 2-bromopyridine (4.8 g, 30.33 mmol), 3-bromophenyl boronic acid (4.06 g, 20.22 mmol), glyme (35 mL), tetrakis(triphenylphosphine)palladium(0) (0.4 g) and a solution of potassium carbonate (7.6 g, 55 mmol) in water (35 mL) was stirred well at reflux under nitrogen overnight. After cooling, the reaction mixture was diluted with ethyl acetate (600 mL) and washed with water (3×200 mL). The solvent and excess 2-bromopyridine were removed on a rotary evaporator (bath temperature=75° C.) and the crude product was purified by chromatography on silica (110 g) with 2% ethyl acetate in heptane (6 L) to produce 1 (3.55 g, 75%).
Reaction SMILES: O[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([C:13]2[O:26][C:2]3[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=3[N:12]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1cccc(NC(=O)c2ccc(-c3ccccn3)cc2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2nc(-c3ccc(-c4ccccn4)cc3)oc12
Yield: 17.2 %

Procedure:
Methyl 2-hydroxy-3-(4-(pyridin-2-yl)benzamido)benzoate (1.04 g, 3 mmol) and 4-methylbenzenesulfonic acid monohydrate (1.2 g, 6 mmol) were added to toluene (20 mL) and the mixture was stirred under reflux for 2 days. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 20:1 to 10:1). 170 mg of solid of methyl 2-(4-(pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxylate was obtained. Yield: 17%. LC-MS (ESI) m/z: 331 (M+1)+.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH:3]1[NH:7][CH2:6][CH2:5][O:4]1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16](=[S:18])=[S:17].C([O-])(=O)C.[Zn+2:23].C([O-])(=O)C>O>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:1][C:2]([Cl:9])([Cl:8])[CH:3]1[N:7]([C:16]([S-:18])=[S:17])[CH2:6][CH2:5][O:4]1.[Cl:1][C:2]([Cl:9])([Cl:8])[CH:3]1[N:7]([C:16]([S-:18])=[S:17])[CH2:6][CH2:5][O:4]1.[Zn+2:23]
Reactant: ClC(Cl)(Cl)C1NCCO1
Reactant: S=C=S
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Solvent: c1ccncc1
Product: S=C([S-])N1CCOC1C(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
Thirty and four-tenth grams (0.160 mole) of 2-trichloromethyloxazolidine (preparation described by W. Ruske and I. Hartmann, J. Prakt. Chem. 18, 146 (1962) was dissolved in 480 g. of pyridine. With rapid stirring at room temperature, 14.4 g. (0.184 mole) of carbon disulfide was added dropwise followed by 15.2 g. (0.083 mole) of anhydrous zinc acetate. The reaction mixture was heated 3 hours at 45°- 50°C, cooled to room temperature, and then diluted with 1 liter water; the precipitated product was filtered and dried in vacuo at room temperature to obtain 33.4 g. of the desired pyridine adduct melting at 205°- 207°C (decomp.). A small analytical sample, recrystallized in methanol, sintered at 209°C and melted with decomposition at 212°-214°C. It had the following anaylsis: Found: C, 26.70; H, 2.74; N, 6.30; S, 19.60; Cl, 31.37; Zn, 9.55%. Calcd for C10H10Cl6N2O2S4Zn . C5H5N: C, 26.65; H, 2.22; N, 6.23; S, 18.95 Cl, 31.54; Zn, 9.68%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[C:4]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[N:3]=1.S(=O)(=O)(O)[OH:22]>>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH2:9])=[O:22])[C:5]([C:10]([F:12])([F:11])[F:13])=[C:4]([C:14]([F:20])([F:19])[C:15]([F:16])([F:17])[F:18])[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1nc(C#N)c(C(F)(F)F)c(C(F)(F)C(F)(F)F)n1
Product: Cc1nc(C(N)=O)c(C(F)(F)F)c(C(F)(F)C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
4.70 g (15.4 mmol) of 2-methyl-6-(pentafluoroethyl)-5-(trifluoromethyl)pyrimidine-4-carbonitrile are dissolved in 80 ml of concentrated sulphuric acid. The reaction mixture is stirred for 12 hours at 100° C. and then added to 300 ml of ice water. The aqueous phase is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulphate and the solvent is concentrated by evaporation under reduced pressure on a rotary evaporator. Half of the crude product was purified by, means of flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate=1/1). This gives 0.63 g of 2-methyl-6-(pentafluoroethyl)-5-(trifluoromethyl)pyrimidine-4-carboxamide (13%) as a viscous oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[N:9][C:10]([C:13]([OH:15])=O)=[CH:11][N:12]=2)=[CH:3][CH:2]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])=[CH:21]2.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[ClH:17].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:13]([C:10]3[N:9]=[N:8][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[N:12][CH:11]=3)=[O:15])[CH2:32][CH2:31]1)(=[O:29])=[O:28])=[CH:21]2
Reactant: O=C(O)c1cnc(-c2ccncc2)nn1
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(c1cnc(-c2ccncc2)nn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (10 ml) were suspended 3-(pyridin-4-yl)-1,2,4-triazine-6-carboxylic acid and 1-[(5-chloroindol-2-yl)sulfonyl]piperazine hydrochloride (292 mg) at room temperature. To the reaction mixture were successively added 1-hydroxybenzotriazole (117 mg), N-methylmorpholine (191 μl) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (250 mg), followed by stirring overnight. After completion of the reaction, the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the residue to separate into layers. The organic layer was dried over magnesium sulfate and the filtrate was concentrated. Ethanol was added to the residue. Yellow crystals thus precipitated were collected by filtration and dried, whereby the free form (282 mg) of the title compound was obtained. The free form was suspended in ethanol and the resulting suspension was made acidic by the addition of 1N hydrochloric acid (in ethanol) and a small amount of water. After concentration of the resulting solution, ethanol and ethyl acetate were added and the resulting mixture was concentrated again. Crystals thus precipitated were collected by filtration and dried, whereby the title compound was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:6].[OH-].[K+]>C(O)C>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COc1ccc(NC(=O)NCCCl)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(N2CCNC2=O)cc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 82.6 g (0.32 mol) of 1-chloro-2-[[[(3,4-dimethoxyphenyl)amino]carbonyl]amino]ethane in 800 ml of ethanol was added dropwise a solution of 21.5 g (0.383 mol) of potassium hydroxide in 400 ml of ethanol. The mixture was stirred for two days at room temperature and the precipitate filtered off by suction. The crude product was recrystallized from 1.5 l of ethyl acetate containing 10% methanol; yield, 52.5 g; melting point 168° C.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[CH:18]([C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1)=[CH2:19].S([O-])([O-])(=O)=O.[Mg+2]>>[N:22]1[CH:21]=[C:20](/[CH:18]=[CH:19]/[C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)[CH:25]=[N:24][CH:23]=1
Reactant: C=Cc1cncnc1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: C(=C/c1cccc2c3c([nH]c12)C1CCN(CC1)C3)\c1cncnc1

Procedure:
The product of Example 1B (265 mg, 0.91 mmol), the product of Example 29A (193 mg, 1.82 mmol) and magnesium sulfate (55 mg, 0.46 mmol) were combined and processed as described in Example 1D to provide the title compound as the slower eluting compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.04-2.20 (m, 4 H), 3.04-3.17 (m, 3 H), 3.22-3.30 (m, 2 H), 4.26 (s, 2 H), 7.05 (t, J=7.6 Hz, 1 H), 7.24 (d, J=16.8 Hz, 1 H), 7.31 (dd, J=7.9, 0.9 Hz, 1 H), 7.43-7.47 (m, J=7.3 Hz, 1 H), 7.89 (s, 1 H), 9.02 (d, J=16.1 Hz, 1 H), 9.04 (s, 2 H); MS (APCI) m/z 317 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=2)[C:6]([NH:16][C:17](=[O:19])[CH3:18])=[N:5]1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[C:6]([NH:16][C:17](=[O:19])[CH3:18])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nn(C(C)=O)c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1nn(C(C)=O)c2ccc(N)cc12
Yield: 98 %

Procedure:
The product from Step (b) above (3.0 g, 11.4 mmol) and 5% Pd/C (1 g) were combined in MeOH (40 mL) and hydrogenated uner a balloon of H2 for 3 h. The mixture was filtered through Celite and the filtrate was concentrated to give the title compound as a dark solid (2.6 g, 98%). NMR 1H NMR (400 MHz, DMSO-D6) δ 10.62 (s, 1H), 7.97 (dd, J=7.9, 1.8, 1H), 6.93-6.89 (m, 2H), 5.26 (s, 2H), 2.52 (s, 3H), 2.08 (s, 3H) (MS m/z 233.2 [M+H]+