Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:48]=[C:49]3[CH:55]=[CH:54][NH:53][C:50]3=[N:51][CH:52]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH:53]1[C:50]2=[N:51][CH:52]=[C:47]([C:2]3[C:10]4[C:9]([NH:11][C@H:12]([C:14]5[N:19]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)[C:18](=[O:26])[C:17]6=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]6[N:15]=5)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=3)[CH:48]=[C:49]2[CH:55]=[CH:54]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cnc5[nH]ccc5c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 48 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (103 mg, 0.17 mmol) was treated with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (103 mg, 0.42 mmol), sodium carbonate (51 mg, 0.48 mmol), 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (43 mg, 0.05 mmol) in 1,2-dimethoxyethane (4 ml) and water (1 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 55 mg (48% yield, 96% purity) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][NH:3]1.[H-].[Na+].Br[CH:14]([C:18]#[N:19])[C:15]([CH3:17])=[CH2:16]>CN(C)C=O>[O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]1[CH2:16][C:15]([CH3:17])=[CH:14][C:18]#[N:19]
Reactant: C=C(C)C(Br)C#N
Reactant: O=c1[nH]sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=CC#N)Cn1sc2ccccc2c1=O
Reaction time: 0.25 h
Yield: 23 %

Procedure:
10.0 g (66 millimoles) of 2,3-dihydro-3-oxo-1,2-benzisothiazole were suspended in 140 ml of dimethylformamide, and 2.0 g (66 millimoles) of 80% strength sodium hydride were added a little at a time, while stirring thoroughly. After 15 minutes, 12.8 g (80 millimoles) of 3-bromo-2-methyl-3-cyanoprop-1-ene were slowly added dropwise, and the reaction mixture was stirred for 2 hours at 80° C. and then cooled. The solvent was distilled off under reduced pressure, the mixture was taken up in ice-water and extracted with methylene chloride, and the organic phase was washed thoroughly with H2O, dried and evaporated down. The crude product (16 g of a dark oil) was then purified by column chromatography (silica gel, mobile phase 95:5 mixture of methylene chloride and methanol). 3.5 g (23%) of 3-(2,3-dihydro-3-oxo-1,2-benzisothiazol-2-yl)-1-cyano-2-methylprop-1-ene of melting point 128°-130° C. were obtained.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:15]([C:19]1([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[O:24][C:23](=[O:25])[CH:22](Cl)[C:21](=[O:27])[CH2:20]1)[CH2:16][C:17]#[CH:18]>CN(C=O)C>[CH2:15]([C:19]1([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[O:24][C:23](=[O:25])[CH:22]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:21](=[O:27])[CH2:20]1)[CH2:16][C:17]#[CH:18]
Reactant: C#CCCC1(C2CCCC2)CC(=O)C(Cl)C(=O)O1
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCCC1(C2CCCC2)CC(=O)C(Sc2ccccc2)C(=O)O1
Yield: 35.8 %

Procedure:
A solution of thiophenol (0.23 mL, 2.2 mmol), triethyl amine (0.156 mL, 1.1 mmol), and 6-but-3-ynyl-3-chloro-6-cyclopentyl-dihydro-pyran-2,4-dione (0.30 g, 1.1 mmol; prepared as described in step 1 above) in DMF (3 mL) was stirred at room temperature for 2 hours. The reaction was then concentrated by rotary evaporation, and then chromatographed (40 g silica gel, gradient elution from 40% EtOAc/Hexanes to 75% EtOAc/Hexanes) to yield the title compound (135 mg, 36%). 1H NMR (CDCl3): δ1.31-1.80 (m, 9H); δ1.96-2.00 (m, 2 H); δ2.03-2.11 (3H, m); δ2.85 (2H, dd, J1=17.94, J2=27.03); δ7.13-7.36 (5H, m). Anal. Calcd. for C20H22O3S.0.1 MeOH.0.15 CH2Cl2: C, 67.86; H, 6.38; S, 8.95. Found C, 68.08; H, 6.48; S, 8.52. ESIMS (M+Na+): 365.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1>ClCCl>[F:15][C:13]1[CH:14]=[C:9]([NH:8][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[CH:10]=[N:11][CH:12]=1
Reactant: Nc1cncc(F)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cncc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
Pivaloyl chloride (18.8 mL, 153 mmol) was added to a solution of 3-amino-5-fluoropyridine (13.2 g, 118 mmol) and TEA (49.2 mL, 353 mmol) in Dichloromethane (235 mL) at 0° C. The reaction was warmed to ambient temperature and stirred for 1 hour. The reaction was quenched with saturated aqueous NaHCO3 and the mixture was extracted with dichloromethane (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to afford the title compound (22.5 g, 115 mmol, 97% yield) as a light brown solid, MS (ESI): m/z=197.35 (MH+), 100% pure by LCMS.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:18][C@@H:17]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[CH3:12])=[CH:7][CH:6]=1)(C)C.COC1N=CC([C@@H](N)C)=CC=1>>[CH3:1][O:4][C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:18][C@@H:17]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[CH3:12])=[CH:7][CH:6]=1
Reactant: CC(C)Oc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Agent: COc1ccc([C@H](C)N)cn1
Product: COc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1

Procedure:
Prepared analogously to Compound 1 using IM46 and commercially available (S)-1-(6-methoxy-pyridin-3-yl)-ethylamine (Supplier Netchem Inc., Catalog No 517706). Yield=0.88 g (66%). 1H NMR (500 MHz, DMSO) δ 8.55 (d, 1H), 8.10 (s, 1H), 7.63 (d, 1H), 7.27 (m, 2H), 7.17 (m, 1H), 7.10 (d, 2H), 6.78 (d, 1H), 4.93 (m, 1H), 3.72 (s, 3H), 2.21 (m, 1H), 1.90 (m, 1H), 1.37 (m, 4H), 1.20 (m, 1H). LC-MS (m/z) 297.4 (MH+), tR=1.36 min (method A).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[C:38]([O:42][C:43](=[O:45])[CH3:44])([CH3:41])([CH3:40])[CH3:39].[Cl:46][C:47]1[CH:52]=[C:51](Cl)[C:50]([CH3:54])=[CH:49][N:48]=1>C1(C)C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd]>[C:38]([O:42][C:43](=[O:45])[CH2:44][C:51]1[C:50]([CH3:54])=[CH:49][N:48]=[C:47]([Cl:46])[CH:52]=1)([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(=O)OC(C)(C)C
Reactant: Cc1cnc(Cl)cc1Cl
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1cnc(Cl)cc1CC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Hexamethyl disilazane (1.33 g, 8.23 mmol) is dissolved in dry toluene (15 ml) under an atmosphere of argon. After thoroughly purging the solvent with argon, the solution is cooled to −78° C., and n-BuLi (5.1 ml of a 1.6 M solution in hexanes, 8.23 mmol) is added. The mixture is stirred for 15 minutes at −78° C. and for 15 minutes at rt, whereupon a clear solution is obtained. Palladium dibenzylideneacetone (Pd2(dba)3, 151 mg, 0.16 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (136 mg, 0.35 mmol) are added. The mixture is stirred for 10 minutes at RT, then it is cooled to −10° C. Acetic acid tert-butyl ester (924 mg, 7.96 mmol) is slowly added heat. After 10 minutes at −10° C., 2,4-dichloro-5-methyl-pyridine (889 mg, 5.49 mmol) is added in one portion. The reaction mixture is allowed to warm to RT. After 1 h, TLC analysis indicated complete consumption of starting materials. The reaction mixture is diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. The organic layer is separated, washed with brine, dried over Na2SO4, and the solvent is evaporated. The residue is purified by FCC (hexanes/EtOAc, gradient from 100:0 to 90:10) to afford the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.45 (s, 9H), 2.26 (s, 3H), 3.52 (s, 2H), 7.18 (s, 1H), 8.18 (s, 1H). ES+−MS: 242.2, 244.2 (Cl) [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)C1CCC(O)CC1
Reaction time: 16 h

Procedure:
To a solution of 4-hydroxycyclohexane carboxylic acid (19.95 g, 138.4 mmol) in 100 mL of degassed DMF was added potassium carbonate (21.0 g, 152.2 mmol) and benzyl bromide (15.61 mL, 131.4 mmol). After 16 hours at room temperature, the reaction mixture was poured into 500 mL of water and extracted 3 times with EtOAc. The combined organic layers were washed with water and brine prior to drying over sodium sulfate. Filtration and solvent removal provided benzyl 4-hydroxycyclohexane carboxylate as a clear oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:16]([C:17]#[N:18])=[CH:15][NH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:14]2[CH:15]=[C:16]([C:17]#[N:18])[C:12]([NH:11][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=3)=[N:13]2)=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)c1ccc(Nc2n[nH]cc2C#N)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Nc2nn(-c3ccc(Cl)cc3)cc2C#N)cc1

Procedure:
3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile (64 mg, 0.244 mmol), copper(II) acetate (66.5 mg, 0.366 mmol), (4-chlorophenyl)boronic acid (76 mg, 0.488 mmol) and pyridine (0.079 mL, 0.976 mmol) were stirred in DCM (8 mL) at room temperature overnight. 2 N HCl was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue twice by MPLC (5-60% EtOAc-hexanes) gave 1-(4-chlorophenyl)-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile as a white solid. 1-(4-chlorophenyl)-5-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile was also isolated.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[CH3:11]C1C=CC(S(O)(=O)=O)=CC=1.CC(=O)OCC>C(OC)(OC)OC>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CNc1nc(Cl)ccc1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: CCOC(C)=O
Product: Cn1cnc2ccc(Cl)nc21
Reaction time: 3 h
Yield: 2681.7 %

Procedure:
To a solution of 6-chloro-N2-methylpyridine-2,3-diamine (300 mg, 1.9 mmol) in HC(OMe)3 (10 mL) was added TsOH (10 mg) at 22° C. The mixture was stirred for 3 h under reflux until TLC (PE: EA=3:1) showed that the reaction was complete. The mixture was concentrated to get the crude material which was purified by using column chromatography on silica gel to give the desired product (261 mg, 81.6%) as an oil. LCMS (m/z): 168.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:9][C:10]([C:13]1[CH:14]=[C:15]([S:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[S:30][CH2:31][C:32](N(C)CCC2C=CC=CN=2)=[O:33])[CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)([CH3:12])[CH3:11]>>[CH3:22][C:19]([C:17]1[CH:16]=[C:15]([S:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[S:30][CH2:31][C:32]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:33])[CH:14]=[C:13]([C:10]([CH3:9])([CH3:11])[CH3:12])[CH:18]=1)([CH3:20])[CH3:21]
Reactant: NCc1ccccn1
Reactant: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2SCC(=O)NCc2ccccn2)cc(C(C)(C)C)c1

Procedure:
Substituting 2-(aminomethyl)pyridine for the 2-(2-methylaminoethyl)pyridine of Example 16, and following the procedure described therein, gives trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N-(2-pyridinylmethyl)-acetamide.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]2[CH:18]=1)=[O:5])C.O.[OH-].[Na+].Cl>C(O)C>[OH2:3].[CH:18]1[N:9]2[C:10]3[C:15]([CH:16]=[CH:17][C:8]2=[N:7][C:6]=1[C:4]([OH:5])=[O:3])=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CCOC(=O)c1cn2c(ccc3ccccc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c(ccc3ccccc32)n1
Temperature: 25 °C

Procedure:
2 g of ethylimidazo-[1,2-a]-quinoline-2-carboxylate were suspended in 40 ml of ethanol and 20 ml of water and 9 ml of N NaOH were added. The mixture was heated on a steam bath for 30 minutes and the hot solution was acidified with 9.5 ml of N hydrochloric acid. The mixture was cooled slowly to room temperature and then in ice to give colorless needles of imidazo-[1,2-a]-quinoline-2-carboxylic acid monohydrate melting at 234°-236° C. The I.R. spectrum suggested that the compound existed partially in the zwitterionic form.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([S:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])(=[O:15])=[O:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].Br[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([S:13]([CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: BrCCCCc1ccccc1
Reactant: COC(=O)CS(=O)(=O)c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCCCc1ccccc1)S(=O)(=O)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
To a suspension of 60% NaH (0.23 g, 5.84 mmol) in anhydrous DMF (15 mL) is added a solution of methyl (3,4-dimethoxyphenylsulfonyl)acetate in 20 mL of DMF (1.6 g, 5.84 mmol) dropwise over 10 minutes. The mixture is stirred at room temperature for 20 minutes. 1-Bromo-4-phenylbutane (1.6 g, 5.84 mmol) is added and the mixture is stirred at room temperature for 24 hours. The mixture is added to 5% HCl and is extracted with ether. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo and the residue is chromatographed on silica gel (7:3 hexane:ethyl acetate) to afford methyl 2-[(3,4-dimethoxyphenyl)sulfonyl]-6-phenylhexanoate (1.3 g, 55%): 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.30-1.42 (m, 2H), 1.52-1.68 (m, 2H), 1.95-2.12 (m, 2H), 2.48-2.68 (m, 2H), 3.64 (s, 3H). 3.92 (d, 7H), 6.95 (d, 1H), 7.07-7.18 (m, 2H). 7.20-7.30 (m. 4H), 7.44 (d, 1H); MS (EI) m/e 406 (M+).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][C:27]1([C:30]([OH:32])=[O:31])[CH2:29][CH2:28]1.C[O-].[Na+].Cl>CO.O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][C:27]2([C:30]([OH:32])=[O:31])[CH2:29][CH2:28]2)=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NCC1(C(=O)O)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1nc(C(=O)NCC2(C(=O)O)CC2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 25.7 %

Procedure:
After a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (101 mg, 0.318 mmol), 1-aminomethyl-cyclopropanecarboxylic acid (110 mg, 0.955 mmol, prepared according to literature: Ohno, Mitsuru et al Synlett 1991, 919-920), and NaOMe in MeOH (1.6 mL, 0.5 M solution) was microwaved at 120° C. for 1 h, the reaction mixture was cooled, diluted with water and acidified with 2 M HCl aqueous solution, the resulted solids were collected via filtration, water-washed and air-dried to give solids, which were further column purified to give the desired product (33 mg). LC MS ESI+: 404 (M+1)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:40][C:35]3[C:36]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(I)cc3)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccc(I)cc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 620.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([SH:19])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:31](Br)[C:32]#[CH:33]>O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19][CH2:33][C:32]#[CH:31])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: FC(F)(F)c1cnc(-c2ccc(Cl)c(S)c2)c(Cl)c1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCSc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reaction time: 16 h

Procedure:
2.0 g of 3-chloro-2-(4-chloro-3-mercaptophenyl)-5-trifluoromethylpyridine (prepared as in Example 33) and 2.1 g of potassium carbonate were introduced into 50 ml of anhydrous dimethylformamide amide at 23° C. After a dropwise addition of 0.73 g of propargyl bromide, the mixture was stirred for 16 h and then poured into 300 ml of water. After 30 minutes, the crystals which had formed were removed, washed with water and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[F:8].CCN(CC)CC.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=1)(=[O:21])=[O:20]
Reactant: OCc1ccc(F)c(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(F)c(Br)c1
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of (3-bromo-4-fluorophenyl)methanol (53 g, 0.258 mol) in DCM (500 mL) at 0° C. was added Et3N (108 mL, 775 mmol, 3 eq) and methanesulfonyl chloride (24 mL, 310 mmol, 1.2 eq) successively. After stirring 30 min, the reaction mixture was partitioned in DCM and water. The organic layer was dried over MgSO4 and evaporated in vacuo to give 3-bromo-4-fluorobenzyl methanesulfonate (60 g), which used to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.65-7.62 (m, 1H), 7.37-7.33 (m, 1H), 7.16 (t, J=4.4 Hz, 1H), 5.17 (s, 2H), 2.99 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH:6]([O:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24](=[O:29])(=[O:28])[N:25]([CH3:27])[CH3:26])[NH:13][C:12]=2[CH:11]=1)([CH3:8])[CH3:7]>>[CH:6]([O:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24](=[O:28])(=[O:29])[N:25]([CH3:27])[CH3:26])[N:13]([CH2:2][CH2:3][CH2:4][Cl:5])[C:12]=2[CH:11]=1)([CH3:8])[CH3:7]
Reactant: CC(C)Oc1ccc2c(c1)Nc1cccc(S(=O)(=O)N(C)C)c1S2
Reactant: ClCCCBr
Product: CC(C)Oc1ccc2c(c1)N(CCCCl)c1cccc(S(=O)(=O)N(C)C)c1S2
Yield: 96.6 %

Procedure:
Crude 2-isopropoxy-6-dimethylsulphamoyl-10-(3-chloropropyl)phenothiazine (60.8 g.) is prepared by reacting 1-bromo-3-chloropropane (80.8 g.) with 2-isopropoxy-6-dimethylsulphamoylphenothiazine (m.p. 187°-189°C.; 52.0 g.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:9][CH3:10])=[CH:4][CH:3]=1.[Br:18]Br.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[C:9]([Br:18])[CH3:10])=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CC=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(Br)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
Into a reactor were introduced 2.00 g (8.69 mmol) of the 1,1-bis(4-fluorophenyl)propene and 25 mL of 1,2-dichloroethane under a nitrogen atmosphere. The contents were cooled to −20° C. A mixture of 1.39 g (8.69 mmol) of bromine and 12 mL of 1,2-dichloroethane was added dropwise thereto over 1 hour, and the resultant mixture was stirred at that temperature for 1 hour and then at room temperature for 16 hours. Subsequently, a solution prepared by mixing 0.703 mL (8.69 mmol) of pyridine with 20 mL of toluene was added dropwise thereto over 15 minutes, and this mixture was stirred at 100° C. for 2 hours and then cooled. Saturated aqueous sodium hydrogen carbonate solution was added to the resultant reaction mixture, which was then extracted with toluene. The resultant organic layer was washed with saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol to obtain 1.21 g (45%) of the target compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[S:19][CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=4)=[CH:13][CH:14]=3)[C:9]([CH3:26])=[C:8]2[CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([O:31]C)=[O:30])=[CH:4][CH:3]=1.C1COCC1.[Li+].[OH-].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[S:19][CH:20]=[C:21]([CH:23]([CH3:24])[CH3:25])[N:22]=4)=[CH:13][CH:14]=3)[C:9]([CH3:26])=[C:8]2[CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([OH:31])=[O:30])=[CH:35][CH:36]=1
Reactant: COC(=O)C(C)(C)Cc1c(C)c2cc(OCc3nc(C(C)C)cs3)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3nc(C(C)C)cs3)cc12

Procedure:
A solution of the ester (70 mg) from Step 1, 2 mL THF, 1 mL MeOH, and 1 mL 2N LiOH was stirred for 24 hours at room temperature. The mixture was poured onto 1N HCl, extracted 2× EtOAc, washed 2× brine, dried (MgSO4), and evaporated. The product was recrystallized from Et2O/hexane to give the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[N:5][N:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=1.[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+:21]>O>[Ag:21].[NH2:1][C:2]1[N:6]=[N:5][N:4]([S:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=1
Reactant: [Ag+]
Agent: Nc1cn(SCc2ccccc2)nn1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [Ag]
Temperature: 50 °C

Procedure:
11.3 g of 5-amino-3-benzylthiotriazole, 1.1 g of sodium hydroxide and 10 g of gelatin were dissolved in 1000 L of water, and the solution was maintained at 50° C. under agitation. Subsequently, a solution obtained by dissolving 8.5 g of silver nitrate in 100 mL of water was added to the above solution over a period of 2 min. The pH of the mixture was regulated so as to precipitate an emulsion, and excess salts were removed. Thereafter, the pH was adjusted to 6.0. Thus, a 5-amino-3-benzylthiotriazole silver salt emulsion was obtained with a yield of 400 g.