Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[N+:21]([O-])=O)(=[O:4])=[O:3].[H][H]>C(#N)C.[Pt]>[CH3:1][S:2]([CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[NH2:21])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)CCOCCNc1c([N+](=O)[O-])cnc2ccccc12
Reactant: [H][H]
Agent: [Pt]
Solvent: CC#N
Product: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12

Procedure:
Solid Pt/C (0.9 g of 5%) was added to a suspension of N-{2-[2-(methylsulfonyl)ethoxy]ethyl}-3-nitroquinolin-4-amine (9 g, 26.5 mmol) in acetonitrile (133 mL) in a Parr vessel. The vessel was placed on a shaker and then pressurized with hydrogen to 50 psi (3.4×105 Pa). After 3 hours the reaction mixture was purged with nitrogen and then filtered through a layer of CELITE filter agent. The filter cake was washed with acetonitrile (200 mL) until the washes were clear. The filtrate was concentrated under reduced pressure to provide N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine as a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-:27].[Na+]>O>[C:1]1([CH2:7][CH:8]([NH:13][C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:25])[CH2:9][O:10][CH2:11][C:12]([OH:14])=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: [OH-]
Reactant: O=C1COCC(Cc2ccccc2)N1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)COCC(Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-5-(Phenylmethyl)-3-morpholinone, (U.S. Pat. No. 3,265,688) 5 g 0.026 mol), is suspended in a solution of 50 ml of concentrated hydrochloric acid and 50 ml of water and refluxed for six hours, cooled to room temperature and extracted with 200 ml of dichloromethane. The aqueous layer is separated, evaporated in vacuo, the residue dissolved in 200 ml of water, and the pH adjusted with a 10% aqueous solution of sodium hydroxide to pH 10-10.5. The solution is cooled to 5° C. and 5.1 g (0.03 mol) of benzylchloroformate is added dropwise while the pH is maintained at pH 10 with a 10% aqueous solution of sodium hydroxide. The mixture is stirred one hour, extracted with 100 ml of diethylether, the aqueous layer is separated and the pH is adjusted to pH 3-4 by the addition of a 10% aqueous solution of hydrochloric acid. The mixture is extracted with dichloromethane, 3×200 ml. The dichloromethane layer is separated, washed with a saturated aqueous solution of sodium chloride, 3×200 ml, separated, dried over sodium sulfate, evaporated and the residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (95:5) to give (±)-[3-phenyl[-2-[[(phenylmethoxy]carbonyl]amino]propoxy]acetic acid, 4 g; mp 96°-100°.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].OO.NC(N)=[O:20].FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[N+:1]([C:4]1[C:5]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N+:6]([O-:20])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccnc1-c1ccccc1
Reactant: NC(N)=O
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc[n+]([O-])c1-c1ccccc1
Temperature: 10 °C
Reaction time: 0.75 h
Yield: 75.3 %

Procedure:
In a 250 mL three-necked round-bottomed flask equipped with a thermometer, droppingbfunnel and a condensor, 11.62 g of 3-nitro-2-phenyl-pyridine is dissolved in 58.0 ml of dichloromethane. Then, 13.65 g of H2O2 urea adduct is added. Under cooling with an ice/water bath, 16.40 ml trifluoroacetic acid anhydride is added dropwise over 25 minutes (temperature below 12° C.). After stirring at 10° C. for 45 minutes, the cooling bath is removed and the mixture is stirred at an ambient temperature for 18 hours. Afterwards, 150 ml of water is added (pH about 1) and extraction is carried out with dichloromethane (3×100 ml). After washing the organic phase with 10% aqueous sodium sulfite solution, it is dried over Na2SO4. After purification by chromatography on a pad of silica gel (eluent: first dichloromethane, then ethyl acetate), 9.45 g of the title compound is obtained as a yellow-green solid (MP: 116-117° C.).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:14]([F:15])=[C:13]2[NH:16][C:17](=[O:39])[C:18]3([CH:22]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=4[F:30])[CH:21]([C:31](O)=[O:32])[NH:20][CH:19]3[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:64][C:65]1[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[CH:67][CH:66]=1>>[C:69]([C:68]1[CH:71]=[CH:72][C:65]([NH:64][C:31]([CH:21]2[NH:20][CH:19]([CH2:34][C:35]([CH3:36])([CH3:38])[CH3:37])[C:18]3([C:12]4[C:13](=[C:14]([F:15])[C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:16][C:17]3=[O:39])[CH:22]2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[F:30])=[O:32])=[CH:66][CH:67]=1)#[N:70]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1c2ccc(Cl)c1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1c2ccc(Cl)c1F
Yield: 33.3 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-7-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 174 (0.4 g, 0.67 mmol), was reacted with diisopropylethylamine (0.43 g, 3.4 mmol), diphenylphosphinic chloride (0.32 g, 1.3 mmol) at room temperature, then reacted with 4-aminobenzonitrile (Aldrich) (0.12 g, 1 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-7-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a yellow solid (Yield 0.13 g, 33%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[CH3:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[CH3:18]>>[OH:4][C:3]([C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([CH3:11])[CH:13]=1)([C:5]([F:8])([F:7])[F:6])[C:2]([F:10])([F:9])[F:1]
Reactant: Cc1ccccc1C
Reactant: O=C(C(F)(F)F)C(F)(F)F
Product: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1C

Procedure:
This compound was prepared from o-xylene and hexafluoroacetone: bp 101°-102°/20.0 mm Hg; ND25 1.4334; lit. (1) bp 200-200.5°/760 mm Hg.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:11][CH3:12])=[O:10])[CH:4]=1.S(Cl)([Cl:15])=O>ClCCl>[ClH:15].[Cl:15][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:11][CH3:12])=[O:10])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CNC(=O)c1cc(CO)ccn1
Solvent: ClCCl
Product: CNC(=O)c1cc(CCl)ccn1
Product: Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
10 g (45.32 mmol) of 4-(hydroxymethyl)-N-methylpyridine-2-carboxamide (Example 40A) were suspended in 160 ml of dichloromethane and cooled to 0° C. 16.18 g (135.96 mmol) of thionyl chloride were added, and the reaction mixture was then warmed to RT and stirred at RT overnight. The reaction mixture was evaporated and dried under high vacuum.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:19]2[C:18]([CH3:17])=[CH:22][N:21]=[CH:20]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cncn1-c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of p-nitrofluorobenzene (2 g, 14 mmol) in DMF (20 mL) was treated with potassium carbonate (8 g, 58 mmol) and 4-methylimidazole (1.2 g, 14.mmol). After refluxing for 18 h, the reaction mixture was cooled down and concentrated at reduced pressure. The residue was treated with water and the mixture was extracted with ethyl acetate and dried over magnesium sulphate. The organic layer was concentrated and the residue was purified by flash-chromatography (methanol/methylene chloride, 0.5:9.5) affording 1.8 g(62%) of p-nitro-4 (5)-methyl-imidazol-1-yl as 7:1 mixture of regioisomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:13][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[C:15](=[O:16])[C:11]=2[C:10]([O:28]CC2C=CC(OC)=CC=2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[OH:28][C:10]1[C:11]2[C:15](=[O:16])[N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:13][C:12]=2[C:3]([O:2][CH3:1])=[C:4]2[C:9]=1[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: COc1ccc(COc2c3c(c(OC)c4cccnc24)CN(Cc2ccc(C(F)(F)F)cc2)C3=O)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(C(F)(F)F)cc1)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.8 %

Procedure:
To 5-methoxy-9-(4-methoxy-benzyloxy)-7-(4-trifluoromethyl-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 305 (13 mg, 0.026 mmol) dissolved in dichloromethane (0.200 ml) was added triethylsilane (TES, 0.05 ml) and trifluoroacetic acid (TFA, 0.100 ml). After stirring at room temperature for 15 minutes, the reaction mixture was concentrated in vacuo and azeotroped three times with a (1:1) tetrahydrofuran to toluene mixture. The resulting residue was then triturated three times with a (3:1) hexane to ether mixture to afford 9-hydroxy-5-methoxy-7-(4-trifluoromethyl-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 306 (7 mg, 0.014 mmol, 54%). 1H NMR (CD3OD) δ 9.0 (dd, 1H), 8.58 (dd, 1H), 7.60 (d, 2H), 7.40 (d, 2H), 4.80 (s, 2H), 4.50 (s, 2H), 3.95 (s, 3H). 19F NMR δ −63, −76.2. MS: 389.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(O)(=O)C>N1C=CC=CC=1.O>[F:21][C:3]1[C:2]([N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(c5ccc(F)cc5)CC4)cc3nc21
Temperature: 115 °C
Yield: 62.5 %

Procedure:
A suspension of 3.07 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 7.21 g of 4-(4-fluorophenyl)-piperazine in 30 cm3 of pyridine was heated at a temperature around 115° C. for 84 hours. The reaction mixture was concentrated under reduced pressure (20 kPa) at approximately 60° C. The solid obtained was taken up in 50 cm3 of water and 3.5 cm3 of 10% acetic acid were added. The suspension was brought to approximately 100° C. The solidified product was filtered off and washed 3 times with 30 cm3 and 3 times 30 cm3 of warm ethanol. After recrystallizing twice from 65 cm3 of dimethylformamide on each occasion, 2.82 g of 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at about 318-319° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.CCOC(C)=O>[Br:9][CH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1sccc1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1ccsc1CBr
Yield: 46.3 %

Procedure:
2-Methyl-thiophene-3-carbonitrile [see Beaton, et al.; Tetrahedron Lett. 39, 10, 1998, 1227-1230] (1.36 g, 11 mmol), N-bromosuccinimide (2.56 g, 14.4 mmol), and a catalytic amount of benzoyl peroxide were stirred in benzene (30 mL) at 80° C. for 2 h. The solution was diluted with EtOAc, washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated in vacuo. Purification by silica gel chromatography (10% EtOAc/hexanes) gave 1.03 g (46%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.39 (d, 1H, J=5.6 Hz), 7.17 (d, 1H, J=5.6 Hz), 4.79 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.[NH2:19][C:20]1[CH:28]=[C:27]([C:29]2[CH:30]=[C:31]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:32]([Cl:35])=[N:33][CH:34]=2)[CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][N:24]2S(C1C=CC=CC=1)(=O)=O>C(Cl)Cl>[Cl:35][C:32]1[N:33]=[CH:34][C:29]([C:27]2[CH:26]=[C:25]3[C:21]([CH:22]=[N:23][NH:24]3)=[C:20]([NH:19][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)=[O:10])[CH:28]=2)=[CH:30][C:31]=1[NH:36][S:37]([CH3:40])(=[O:39])=[O:38]
Reactant: Cc1cccc(C(=O)O)n1
Reactant: CS(=O)(=O)Nc1cc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2cc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)cc3[nH]ncc23)n1
Reaction time: 0.25 h
Yield: 41.8 %

Procedure:
6-Methyl-2-pyridinecarboxylic acid (43 mg) was dissolved in DCM (2 ml) and 1-chloro-N,N,2-trimethyl-1-propen-1-amine (0.042 ml) was added. The reaction was stirred for 15 mins. N-{5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-chloro-3-pyridinyl}methane sulfonamide (100 mg) in DCM (4 ml) was added and the reaction left at RT. The reaction was evaporated to dryness. IPA (3 ml) was added to the residue followed by 2M NaOH (aq) (3 ml) and the reaction was left overnight. The solution was neutralised using 2M HCl (aq) and then concentrated. The precipitate that formed was filtered then DMSO was added to the precipitate. Attempts to filter the solid failed so the reaction was blown down under a stream of nitrogen. The residue was redissolved in DMSO (0.5 ml) and purified by MDAP (method E). The pure fraction was evaporated to dryness to give title compound (40 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29](=[O:42])(=[O:41])[NH:30][C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[CH:27][C:21]=2[S:20](=[O:44])(=[O:43])[N:19]=1.[CH3:45][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29](=[O:42])(=[O:41])[N:30]([CH3:45])[C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[CH:27][C:21]=2[S:20](=[O:43])(=[O:44])[N:19]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC(=O)OCc4ccccc4)ccc3N2)c(O)c2cccnc21
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)N(C)C(=O)OCc4ccccc4)ccc3N2)c(O)c2cccnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.3 %

Procedure:
A solution of the product of Example 436 (0.032 g, 0.05 mmol) in 1:1 tetrahydrofuran/methanol (2 ml) at −10° C. was treated dropwise with trimethylsilyl diazomethane (2.0 M in hexanes, 50 μL, 0.1 mmol), then stirred at 25° C. for 16 hours and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 3% methanol in dichloromethane to provide the title compound (5 mg, 15% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.99 (d, J=6.25 Hz, 6 H) 1.58 (m, 2 H) 1.69 (m, 1 H) 3.21 (s, 3 H) 4.49 (m, 2 H) 5.19 (s, 2 H) 7.32 (m, 5 H) 7.46 (m, 1 H) 7.51 (dd, J=7.91, 4.60 Hz, 1 H) 7.58 (d, J=2.21 Hz, 1 H) 7.68 (d, J=8.82 Hz, 1 H) 8.57 (dd, J=8.09, 1.84 Hz, 1 H) 8.90 (dd, J=4.78, 1.47 Hz, 1 H) 11.29 (s, 1 H) 14.09 (s, 1 H). MS (ESI−) m/z 653 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:40]([Si:42]([C:47]#[CH:48])([CH2:45][CH3:46])[CH2:43][CH3:44])[CH3:41]>CN(C=O)C.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>[CH2:43]([Si:42]([C:40]#[C:41][C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1)([CH2:47][CH3:48])[CH2:45][CH3:46])[CH3:44]
Reactant: CCOC(=O)Cc1cncnc1Cl
Reactant: C#C[Si](CC)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cncnc1C#C[Si](CC)(CC)CC
Temperature: 120 °C
Yield: 94 %

Procedure:
To a nitrogen de-gassed solution of ethyl 2-(4-chloropyrimidin-5-yl)acetate (I108) (0.823 g, 4.10 mmol) in dry DMF (15 mL) were added triethylamine (1.715 mL, 12.31 mmol) followed by triphenylphosphine (0.124 g, 0.473 mmol), trans-dichlorobis(triphenyl-phosphine)palladium(II) (0.144 g, 0.205 mmol), Cu(I)I (0.078 g, 0.410 mmol) and finally (triethylsilyl)acetylene (1.470 mL, 8.204 mmol). The reaction mixture was then heated under microwave irradiation at 120° C. for 25 minutes, concentrated in vacuo and purified by silica gel chromatography (Isolera Biotage, 40 g Si cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I109) (1.176 g, 94% yield) as a yellow-orange oil; 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.68 (s, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.80 (s, 2H), 1.26 (t, J=7.1 Hz, 3H), 1.10-1.01 (m, 9H), 0.77-0.67 (m, 6H) LCMS Method C: rt 6.64 min; m/z 305.1 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.C(N(CC)CC)C.[CH:30]1([CH2:33][C:34](O)=[O:35])[CH2:32][CH2:31]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.C(#N)C>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:34](=[O:35])[CH2:33][CH:30]4[CH2:32][CH2:31]4)[CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: O=C(O)CC1CC1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCNC3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCN(C(=O)CC4CC4)C3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of (S)-4-amino-5(piperidine-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazin 2,2-dioxide hydrochloride (Example 2a, 694 mg, 2.0 mmol) in H2O/ACN (5 mL, 1:1) was added triethylamine (228 uL, 2.0 mmol). After stirring at room temperature for 5 min a solution of 2-cyclopropylacetic acid (200 mg, 2.0 mmol), HOBt (272 mg, 2.0 mmol), and EDCI-HCl (382 mg, 2.0 mmol) in H2O/ACN (5 mL, 1:1) was added to the mixture. An additional equivalent of triethylamine (228 uL, 2.0 mmol) was added and the reaction mixture was stirred at room temperature overnight. The product crashed out of solution and is collected by vacuum filtration. The compound was purified via preparative RP HPLC (10 to 90% EtOH in water) then diluted with 10 mL water and 200 mg of NaHCO3 was added. The solution was heated at 90° C. for 20 minutes until all the compound was dissolved then cooled to 0° C. and neutralized with 1N HCl solution. The product precipitated out and was collected by filtration and dried to provide the title compound (410 mg, 52.3%). 1H NMR (DMSO-d6, 400 MHz, 80° C.): 0.12 (br s, 2H), 0.44 (m, 2H), 0.96 (br s, 1H), 1.42 (m, 2H), 1.70 (m, 1H), 1.88 (m, 1H), 1.98 (br s, 1H), 2.09 (m, 1H), 2.26 (br s, 2H), 2.91 (m, 2H), 3.67 (br s, 0.5H), 3.85 (br s, 0.5H), 4.09 (m, 3H), 6.65 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 7.46 (t, J=8.4 Hz, 1H), 7.75 (br s, 1H), 8.16 (br s, 1H), 10.79 (s, 1H). M+H=393.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:1].[ClH:1].[N:23]1([CH2:22][CH2:21][NH:20][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:3]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: COc1ccc(-c2cc3ccccc3c(Cl)n2)cc1
Reactant: NCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3ccccc3c(NCCN3CCOCC3)n2)cc1
Product: Cl
Temperature: 120 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
1-Chloro-3-(4-methoxyphenyl)isoquinoline (405 mg) and 4-(2-aminoethyl)morpholine (394 mg) were dissolved in N,N-dimethylformamide (5 ml), followed by the addition of potassium carbonate (415 ml), and the resulting mixture was stirred at 120° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system). Then, the resulting product was converted into a hydrochloride in a conventional manner, and then recrystallized from ethanol/isopropyl ether, to give the hydrochloride of the title compound as pale yellow crystals (190 mg, yield; 27%).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][O:18][C:19]1[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=1.C(O)C(N)(CO)CO>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][O:18][C:19]1[CH:20]=[C:21]([NH:25][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(OCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Reactant: CC(C)C(=O)Cl
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(OCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Isobutyryl chloride (11 mg, 0.1 mmol) was added to a solution of 3-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethoxy]-phenylamine (see Example 21) (30 mg, 0.09 mmol) in CH2Cl2 (1 mL). The reaction was shaken at room temperature. After 72 h, trisamine resin (79 mg, 0.1 mmol) was added and the reaction was shaken for another 4 h. The reaction was filtered and the resin was washed with CH2Cl2 (2 mL). The filtrates were combined and concentrated in vacuo. Preparative TLC (silica, 20:1 CH2Cl2:MeOH, Rf=0.4) provided N-{3-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethoxy]-phenyl}-isobutyramide, 24a as a white solid (15 mg, 40%); MS m/z 418 [C21H21Cl2N3O2+H]+.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([N+:14]([O-])=O)[CH:5]=1)#[N:3].[H][H]>CO.O=[Pt]=O>[Cl-:1].[NH2:14][C:6]1[CH:5]=[C:4]([CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH2:2][NH3+:3]
Reactant: COC(=O)c1ccc(C#N)cc1[N+](=O)[O-]
Reactant: [H][H]
Reactant: Cl
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)c1ccc(C[NH3+])cc1N
Product: [Cl-]

Procedure:
After addition of 365 ml of concentrated hydrochloric acid (4.37 mol) and 9 g of PtO2, a suspension of 900 g (4.37 mol) of methyl 4-cyano-2-nitrobenzoate in 13.5 l of methanol is first hydrogenated at room temperature at a hydrogen pressure of 1 bar. After the hydrogen uptake has subsided, the pressure is increased to 17 bar, and hydorgenation is continued until the hydrogen uptake is complete. For work-up, the pressure is released to atmospheric pressure, the catalyst is removed by filtration through silica gel and the filtrate is concentrated completely in vacuo. Digestion of the residue with ethyl acetate yields 3-amino-4-methoxycarbonylbenzylammonium chloride, yield 757 g (80%), melting point 185-190° C. (decomp.).