Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].C(OC(=O)[NH:19][CH:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][C:29]3[NH:32][CH:33]=[CH:34]C=3N=2)[CH2:22][CH2:21]1)(C)(C)C.[Al+3].[Cl-].[Cl-].[Cl-].CO.ClC1C(Cl)=CC=CC=1C1[CH:51]=[N:52]OC=1C1C2C(=NC=CC=2)NC=1>C(Cl)Cl>[NH2:19][CH:20]1[CH2:21][CH2:22][CH:23]([C:26]2[CH:31]=[C:30]3[C:34]([C:10](=[O:11])[CH2:9][C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[F:1])=[CH:33][NH:32][C:29]3=[N:52][CH:51]=2)[CH2:24][CH2:25]1
Reactant: Clc1cccc(-c2cnoc2-c2c[nH]c3ncccc23)c1Cl
Reactant: O=C(Cl)Cc1cccc(F)c1F
Reactant: CC(C)(C)OC(=O)NC1CCC(c2ccc3[nH]ccc3n2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: NC1CCC(c2cnc3[nH]cc(C(=O)Cc4cccc(F)c4F)c3c2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
A solution of 2,3-difluorophenylacetyl chloride (1.0 mmol) in CH2Cl 2(3 ml) was added dropwise to a mixture of [4-(1H-pyrrolo[2,3-]pyridin-5-yl)-cyclohexyl]-carbamic acid tert-butyl ester (280 mg, 0.88 mmol) and AlCl3 (612 mg, 4.6 mmol) in CH2Cl2(15 ml) at 0° C. After the addition, the reaction was stirred for 1.5 hrs at 0° C. Methanol (5 ml) was added to the reaction. After 1 hr. the reaction was evaporated and the resulting residue purified by flash chromatography to afford 1-[5-(4-Amino-cyclohexyl)-1H-pyrrolo[2,3-b]pyridin-3-yl ]-2-(2,3-difluoro-phenyl)-ethanone (229 mg) in 70.5% yield. LC-MS: m/e=370.3 (M+H), 368.4 (M−H). After the treatment of the above cyclohexylamine (220 mg, 0.60 mmol) with 37% formaldehyde (2 ml) and formic acid (4 ml) at 80° C. for 15 h, pure 2-(2,3-Difluoro-phenyl)-1-[5-(4-dimethylamino-cyclohexyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-ethanone was obtained by FC (167 mg) in 70.1% yield. LC-MS: m/e: 398.4 (M+H), 396.4 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14].[H-].[Na+].[C:24]([O:28][CH3:29])(=[O:27])[C:25]#[CH:26].Cl>CN(C)C=O.C(OCC)(=O)C.O>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]/[CH:26]=[CH:25]/[C:24]([O:28][CH3:29])=[O:27])=[CH:7][C:6]=1[NH:12][S:13]([CH3:16])(=[O:14])=[O:15]
Reactant: CS(=O)(=O)Nc1cc(O)ccc1Oc1ccc(F)cc1F
Reactant: C#CC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/Oc1ccc(Oc2ccc(F)cc2F)c(NS(C)(=O)=O)c1
Temperature: 22.5 °C
Reaction time: 0.33 h
Yield: 31.6 %

Procedure:
3 g of 4-(2,4-difluorophenoxy)-3-methylsulfonylaminophenol was dissolved in 15 ml of N,N-dimethylformamide. 420 mg of sodium hydride (purity: 60%) was added. The mixture was stirred for 20 minutes at 20-25° C. Then, 0.88 g of methyl propiolate was added dropwise in about 5 minutes so that the reaction temperature was maintained below 40° C. The mixture was stirred for 30 minutes at 30°-40° C. After the completion of the reaction, 50 ml of water and 50 ml of ethyl acetate were added thereto. The resulting mixture was adjusted to pH 4 with 4N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (eluant: a 20:1 mixture of toluene and ethyl acetate) to obtain 1.2 g (yield: 31.6%) of methyl trans-3-[4-(2,4-difluorophenoxy)-3-methylsulfonylaminophenoxy]acrylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[C:5]([N:7]1[CH2:20][C:19]([CH3:22])([CH3:21])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]([C:23](OCC)=[O:24])[CH2:8]1)=[O:6].[CH:32]1([NH-])[CH2:35][CH2:34][CH2:33]1.C1N=C[N:39](C(N2C=NC=C2)=O)C=1.C1(N)CCC1>>[CH:32]1([CH:20]2[N:7]([C:5](=[O:6])[C:4]3[CH:28]=[CH:29][C:30]([F:31])=[C:2]([F:1])[CH:3]=3)[CH:8]=[C:9]([C:23]([NH2:39])=[O:24])[C:10]3[NH:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]=3[C:19]2([CH3:21])[CH3:22])[CH2:35][CH2:34][CH2:33]1
Reactant: [NH-]C1CCC1
Reactant: CCOC(=O)C1CN(C(=O)c2ccc(F)c(F)c2)CC(C)(C)c2c1[nH]c1ccccc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: NC1CCC1
Product: CC1(C)c2c([nH]c3ccccc23)C(C(N)=O)=CN(C(=O)c2ccc(F)c(F)c2)C1C1CCC1

Procedure:
In a similar manner, ethyl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate was saponified, converted to the corresponding cyclobutylamide using CDI and cyclobutylamine, and then oxidized as described previously in Example 63 to give cyclobutyl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxamide; MS(ESI): 450 (MH+).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH2:4]([NH:8][C:9]1[C:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][C:17]=2[O:24][CH3:25])=[C:13]([CH3:26])[N:12]=[C:11]([NH2:27])[N:10]=1)[CH2:5][CH2:6][CH3:7]>CN(C=O)C.CS(C)=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>[NH2:27][C:11]1[N:10]=[C:9]([NH:8][CH2:4][CH2:5][CH2:6][CH3:7])[C:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:1]#[N:2])=[CH:18][C:17]=2[O:24][CH3:25])=[C:13]([CH3:26])[N:12]=1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CCl)cc1OC
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1OC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
KCN (0.844 g) was added to a stirred solution of the product from step (iv) (2.78 g) in DMF (10 mL) and DMSO (10 mL). The mixture was stirred at rt for 15 h. The reaction mixture was diluted with EtOAc (100 mL) and sat. NaHCO3 (100 mL). The organic phase was separated, dried and solvent removed to give the subtitle compound as a solid, 2.2 g.
Reaction SMILES: [Cl-].C[O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[O-].[Na+].[CH2:27]([O:29][N:30]=[C:31]([CH3:48])[C:32](=[N:34][O:35][C:36]1[C:41]([C:42](=O)[C:43]([O:45][CH3:46])=[O:44])=[CH:40][CH:39]=[CH:38][N:37]=1)[CH3:33])[CH3:28].O.[CH3:50][N:51](C)C=O>>[CH3:4][O:3][N:51]=[C:50]=[C:42]([C:41]1[C:36]([O:35][N:34]=[C:32]([CH3:33])[C:31](=[N:30][O:29][CH2:27][CH3:28])[CH3:48])=[N:37][CH:38]=[CH:39][CH:40]=1)[C:43]([O:45][CH3:46])=[O:44]
Reactant: CCON=C(C)C(C)=NOc1ncccc1C(=O)C(=O)OC
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCON=C(C)C(C)=NOc1ncccc1C(=C=NOC)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 650 mg (1.9 mmol) of methoxymethyltriphenyl-phosphonium chloride and 340 g (1.9 mmol) of sodium methoxide solution (30% strength in methanol) in 8 ml of dimethylformamide was stirred for 10 minutes at room temperature. The reaction mixture was subsequently treated with 400 mg (0.95 mmol) of methyl [2-(2-ethoxyimino-1-methylpropylideneaminooxy)pyridin-3-yl]glyoxylate, dissolved in 4 ml of dimethylformamide. The reaction mixture was stirred for 4 hours at room temperature, hydrolyzed with 20 ml of water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. This gave 120 mg (38%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([OH:5])([CH3:4])[CH3:3].Cl[S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8].[NH2:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[S:22]([N:25]2[CH2:46][CH2:45][C:28]3([N:32]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]([F:43])([F:42])[F:41])[CH:34]=4)[NH:30][C:29]3=[O:44])[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[C:16]([CH3:47])[CH:15]=1.C(N(CC)CC)C>ClCCl>[C:2]([O:5][C:11]([NH:10][S:7]([NH:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[S:22]([N:25]2[CH2:26][CH2:27][C:28]3([N:32]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]([F:41])([F:43])[F:42])[CH:34]=4)[NH:30][C:29]3=[O:44])[CH2:45][CH2:46]2)(=[O:23])=[O:24])=[C:16]([CH3:47])[CH:15]=1)(=[O:9])=[O:8])=[O:12])([CH3:4])([CH3:3])[CH3:1]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1cc(N)ccc1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1cccc(OC(F)(F)F)c1)NC2=O
Reactant: CC(C)(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(NS(=O)(=O)NC(=O)OC(C)(C)C)ccc1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1cccc(OC(F)(F)F)c1)NC2=O
Yield: 60 %

Procedure:
A solution of tBuOH (71.9 mg, 0.97 mmol) in dichloromethane (1.5 ml) was added to a solution of chlorosulfonyl isocyanate (137 mg, 0.97 mmol) in dichloromethane (3 ml) with stirring under ice-cooling. The mixture was stirred at 0° C. for 10 minutes and then added to a solution of 8-[(E)-2-(4-amino-2-methyl-phenyl)-ethenesulfonyl]-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (400 mg, 0.81 mmol) and triethylamine (164 mg, 1.62 mmol) in dichloromethane (3 ml). The mixture was stirred for one hour, and then quenched with water and extracted with dichloromethane. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give N-tert-butoxycarbonyl-N′-(3-methyl-4-{(E)-2-[4-oxo-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-vinyl}-phenyl)-sulfamide (334 mg, 60%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]=O.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH:16]=[O:17])[CH:13]=[CH:12][C:11]=1[OH:18]>C(O)C>[OH:18][C:11]1[C:12]([CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:13][C:14]([CH:16]=[O:17])=[CH:15][C:10]=1[O:9][CH3:8]
Reactant: C1CCNC1
Reactant: COc1cc(C=O)ccc1O
Reactant: C=O
Solvent: CCO
Product: COc1cc(C=O)cc(CN2CCCC2)c1O

Procedure:
21.3 g (0.30 mol) of pyrrolidine were added to 24.0 g (0.30 mol) of a 37% aqueous formaldehyde solution in 180 ml of ethanol. Then 30.4 g (0.20 mol) of 4-hydroxy-3-methoxybenzaldehyde (vanillin) were added. The mixture was refluxed for three hours. A solid began to precipitate out as early as during cooling, which was filtered out after complete cooling of the reaction batch and dried.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:26])[NH:18][C:19]2[S:20][CH:21]=[C:22]([S:24][CH3:25])[N:23]=2)=[CH:13][CH:12]=1)(=[O:9])[CH3:8]>O.CO>[C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:26])[NH:18][C:19]2[S:20][CH:21]=[C:22]([S:24]([CH3:25])=[O:1])[N:23]=2)=[CH:15][CH:16]=1)(=[O:9])[CH3:8]
Reactant: O=S([O-])OO
Reactant: CSc1csc(NC(=O)c2ccc(OC(C)=O)cc2)n1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)Nc2nc(S(C)=O)cs2)cc1

Procedure:
Using the Oxone® procedure as described in section 1.5.1.7 for the synthesis of compound (I), a solution of Oxone® (3.68 g, 6.00 mmol) is dissolved in a minimum amount of water (30.0 mL) and is added to a cold solution (0° C.) of 512 (0.63 g, 2.0 mmol) dissolved in a minimum amount of methanol (200 mL). Workup and purification by flash chromatography affords 3 as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[CH3:10])C=O.O.C1(C)C=CC(S(O)(=O)=[O:21])=CC=1.OO.S([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CO>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([OH:21])[CH:7]=[C:8]([CH3:11])[C:9]=1[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cc(C=O)c(C)c(Br)c1C
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(O)c(C)c(Br)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
To a solution of 3-bromo-2,4,5-trimethylbenzaldehyde obtained in Reference Example 67 (32.0 g, 141 mmol) in THF (100 mL) was added methanol (200 mL) with ice-cooling, followed by addition of p-toluenesulfonic acid monohydrate (5.40 g, 28.4 mmol) with ice-cooling. Hydrogen peroxide (30%, 24.0 g, 212 mmol) was added dropwise to the reaction solution at 10° C. or lower, and the mixture was warmed to room temperature and stirred for 12 hours. Then the reaction solution was stirred at 50° C. for 36 hours, followed by addition of an aqueous sodium sulfite solution, and methanol and THF were distilled off under reduced pressure. The residue was extracted with ethyl acetate, the organic layer was washed with water and a saturated brine, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 9.1 g (yield 30%) of the title compound. Melting point: 86-88° C.
Reaction SMILES: [I:1]I.ClCl.[OH:5][C:6]1[CH:11]=[C:10]([CH2:12][CH3:13])[N:9]=[CH:8][N:7]=1>C(O)(=O)C>[OH:5][C:6]1[C:11]([I:1])=[C:10]([CH2:12][CH3:13])[N:9]=[CH:8][N:7]=1
Reactant: CCc1cc(O)ncn1
Reactant: II
Agent: ClCl
Solvent: CC(=O)O
Product: CCc1ncnc(O)c1I

Procedure:
50.8 g of iodine (0.20 mol) are introduced into 850 ml of acetic acid, and 14.8 g (0.21 mol) of chlorine are introduced at 30°-33° C., whereupon the iodine dissolves. 49.7 g (0.4 mol) of 4-hydroxy-6-ethylpyrimidine in solution in 150 ml of acetic acid are then added dropwise at 20° C., the crystalline end product separating out. Filtration with suction and recrystallisation from ethyl acetate yield 24.4 g of pure substance, m.p. 191°-192° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:27][CH2:26][CH:25]([NH:28]C(=O)OC(C)(C)C)[CH2:24]2)=[N:21][CH:22]=1.[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([F:52])[C:38]=1[OH:53]>>[NH2:28][CH:25]1[CH2:26][CH2:27][N:23]([C:20]2[N:21]=[CH:22][C:17]([NH:16][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:41]5[CH:40]=[C:39]([F:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12](=[O:15])[CH2:13][CH3:14])=[CH:18][CH:19]=2)[CH2:24]1
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC(N)C2)nc1
Yield: 37.3 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-propionylquinolin-4-ylamino) pyridin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (76 mg, 0.28 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (34 mg, 37% over two steps) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.29 (s, 1H), 8.29-8.18 (m, 2H), 8.06-7.99 (m, 2H), 7.82 (dd, J=9.1, 2.6 Hz, 1H), 7.16-7.10 (m, 1H), 7.07 (s, 1H), 6.97 (d, J=9.1 Hz, 1H), 4.17-4.08 (m, 1H), 4.06-3.98 (m, 1H), 3.90-3.81 (m, 1H), 3.79-3.70 (m, 2H), 3.27-3.19 (m, 2H), 2.64-2.53 (m, 1H), 2.35-2.25 (m, 1H), 1.26 (t, J=7.1 Hz, 3H); ESI MS m/z 506 [C27H25ClFN5O2+H]+; HPLC>99% (AUC), tR=10.75 min.
Reaction SMILES: [CH2:1]([CH:4]1[N:8]([CH2:9][CH3:10])[S:7](=[O:12])(=[O:11])[NH:6][C:5]1=[O:13])[CH2:2][CH3:3].[C:14]1([S:20][CH2:21]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CN(C=O)C>[C:14]1([S:20][CH2:21][N:6]2[C:5](=[O:13])[CH:4]([CH2:1][CH2:2][CH3:3])[N:8]([CH2:9][CH3:10])[S:7]2(=[O:12])=[O:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCC1C(=O)NS(=O)(=O)N1CC
Reactant: ClCSc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCC1C(=O)N(CSc2ccccc2)S(=O)(=O)N1CC
Yield: 73.5 %

Procedure:
A mixture of 4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (3.7 g, 16.6 mmol), phenylthiomethyl chloride (2.9 g, 18.28 mmol) and tetrabutylammonium bromide (0.53 g, 3.1 mmol) suspended in toluene/DMF (90 ml/10 ml) was refluxed for 8 hours, cooled, and concentrated in vacuo. The residue was diluted with water, extracted with ether/ethyl acetate (500 ml, 1:1), and the organic layer was washed with water and brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 4.01 g of 2-phenylthiomethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =H; R2 =propyl; R3 =ethyl) as an oil.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:38]3[N:45]=[C:46]([C:48]([OH:50])=O)[CH:47]=[C:37]3[N:36]=2)=[CH:31][CH:30]=1.[S:51]1[CH:55]=[CH:54][CH:53]=[C:52]1[CH2:56][NH2:57].C(N(CC)CC)C>C1COCC1.C(OCC)C>[S:51]1[CH:55]=[CH:54][CH:53]=[C:52]1[CH2:56][NH:57][C:48]([C:46]1[CH:47]=[C:37]2[N:36]=[C:35]([C:32]3[CH:33]=[CH:34][C:29]([Br:28])=[CH:30][CH:31]=3)[CH:40]=[C:39]([C:41]([F:44])([F:42])[F:43])[N:38]2[N:45]=1)=[O:50]
Reactant: O=C(O)c1cc2nc(-c3ccc(Br)cc3)cc(C(F)(F)F)n2n1
Reactant: NCc1cccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(NCc1cccs1)c1cc2nc(-c3ccc(Br)cc3)cc(C(F)(F)F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
Benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) (0.144 g, 0.327 mmol) was added to a suspension of 5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (0.115 g, 0.298 mmol) and thiophene-2-methylamine (0.034 mL, 0.327 mmol) in THF (10 mL) containing triethylamine (0.124 mL, 0.893 mmol). The reaction mixture was stirred overnight at room temperature, diluted with ethyl ether (5 mL) and washed with a saturated aqueous solution of sodium bicarbonate (10 mL). The organic layer was collected, concentrated under reduced pressure and the crude product was purified by column chromatography to give 5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (thiophen-2-ylmethyl)-amide (0.105 g, 73%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[C:18](\[C:22]#[N:23])/[C:19]([NH2:21])=[O:20])=[C:9]1OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:27].[OH-]>CO>[NH2:23][C:22]1[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]=2[N:27]=1
Reactant: [NH4+]
Reactant: CCOc1c(/C=C(\C#N)C(N)=O)c2ccccc2n1Cc1ccccc1
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cc2c3ccccc3n(Cc3ccccc3)c2nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of (2E)-3-(1-benzyl-2-ethoxy-1H-indol-3-yl)-2-cyanoacrylamide (vi-a, 2.00 g, 5.79 mmol) in MeOH (150 mL) was added NH4OH (30% weight solution of NH3 in water, 100 mL). The reaction was stirred at RT overnight. The reaction was concentrated under reduced pressure and the crude solid was triturated with H2O. The solid was filtered and triturated again with ether. A yellow solid was collected by suction filtration to yield 2-amino-9-benzyl-9H-pyrido[2,3-b]indole-3-carboxamide (vii-a, 1.23 g, 63%). NH4OAc standard conditions. DAD Retention time =7.25 min. M+H=317. 1H NMR (300 MHz, DMSO-d6): δ 8.77 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.62 (br s, 2H), 7.40 (d, J=7.7 Hz, 1H), 7.31-7.16 (m, 9H), 5.52 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](Br)=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cu][C:20]#[N:21]>CN1CCCC1=O>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([C:20]#[N:21])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1cc(Br)c(C(C)C)cc1OCC
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cc(C#N)c(C(C)C)cc1OCC
Yield: 40.3 %

Procedure:
Ethyl 2-ethoxy-4-iso-propyl-5-bromobenzoate (1.2 g, 3.8 mmol) was treated with copper (I) cyanide (682 mg, 7.6 mmol) in N-methyl-2-pyrrolidinone (40 ml) as described in Procedure 5 to give the title compound as an oil (400 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]2[S:14][C:13]([NH2:15])=[N:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.CO[C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27]([OH:29])=O)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1([O:53][C:54](N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]2[S:14][C:13]([NH:15][C:27]([C:24]3([C:21]4[CH:20]=[CH:19][CH:18]=[C:23]([O:53][CH3:54])[CH:22]=4)[CH2:25][CH2:26]3)=[O:29])=[N:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ncccc1Cc1cnc(N)s1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cccc(C2(C(=O)Nc3ncc(Cc4cccnc4OC)s3)CC2)c1
Temperature: 78 °C
Reaction time: 12 h

Procedure:
5-(2-Methoxy-pyridin-3-ylmethyl)-thiazol-2-ylamine (221 mg, 1.00 mmol) and 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid (192 g, 1.00 mmol) were dissolved in acetonitrile (5 mL) containing triethylamine (0.421 mL, 3.00 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 760 mg, 2.0 mmol) was added and the solution was allowed to stir at 78° C. for 12 hours. An aliquot of the crude product was purified by reverse-phase preparative liquid chromatography. ESI-MS m/z calc. 395.1. found; 396.3 (M+1)+ Retention time 3.27 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.C(OCC)(=O)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Cl)nc2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 63.6 %

Procedure:
To a solution of 2-chloro-5-hydroxypyridine (50 g, 0.386 mol) and potassium carbonate (80 g, 0.579 mol) in N,N-dimethylformamide (300 mL) was added p-methoxybenzyl chloride (66.5 g, 0.425 mol), and the mixture was stirred at 80° C. for 4 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with methanol to give the title compound (61.3 g, 64%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][SH:4].[CH2:7]([OH:10])[C:8]#[CH:9].[OH-].[K+].CN(C)C=O>O>[OH:10][CH2:7][CH:8]=[CH:9][S:4][CH2:3][C:2]([F:6])([F:5])[F:1]
Reactant: C#CCO
Reactant: FC(F)(F)CS
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: OCC=CSCC(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2.32 g 2,2,2-trifluoroethanethiol, 1.12 prop-2-yne-1-ol, 300 mg potassium hydroxide and 40 ml dimethylformamide is stirred at ambient temperature for 20 hours. The mixture is poured into 150 ml of water and extracted with 100 ml ethyl acetate (3 times). The organic phase is washed with water, dried and concentrated. The crude product is purified by column chromatography to obtain 75 mg of pure 1-hydroxy-3-(2,2,2-trifluoroethylthio)-prop-2-ene.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:9])[C:6]=1[CH2:7][OH:8].[CH3:10][O:11][C:12]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[CH:15][C:13]=1[NH2:14]>>[NH2:14][C:13]1[CH:15]=[CH:16][C:17]([C:2]2[CH:3]=[N:4][N:5]([CH3:9])[C:6]=2[CH2:7][OH:8])=[CH:18][C:12]=1[O:11][CH3:10]
Reactant: Cn1ncc(Br)c1CO
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Product: COc1cc(-c2cnn(C)c2CO)ccc1N

Procedure:
The title compound was prepared according to the method described for Preparation 158 using (4-bromo-1-methyl-1H-pyrazol-5-yl)methanol (Preparation 222) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. The residue was purified using Biotage silica gel column chromatography eluting with EtOAc followed by elution through an SCX-2 cartridge.