Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:24](O)=[O:25]>>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([CH:24]=[O:25])=[CH:10][CH:11]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: CCC(C)(C)c1ccccc1
Agent: C1N2CN3CN1CN(C2)C3
Product: CCC(C)(C)c1ccc(C=O)cc1

Procedure:
A solution of tert-pentylbenzene (10.04 g, 67.72 mmol) and hexamethylenetetramine (9.49 g, 67.7 mmol) in trifluoroacetic acid (100 ml) was stirred at 90° C. overnight. The reaction solution was evaporated under reduced pressure, diluted with water, alkalified with potassium carbonate, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product of 4-(tert-pentyl)benzaldehyde as a dark brown liquid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>CN(C)C=O>[Cl:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Clc1nccnc1N1CCOCC1

Procedure:
A mixture of 2,3-dichloropyrazine (5 g., 0.034 mmole), morpholine (5.8 g., 0.067 mmole), and 50 ml. of dimethylformamide are heatd at 90°-120° C. for 6-14 hours, in an atmosphere of nitrogen. The reaction mixture is cooled and evaporated to dryness at a water-bath temperature of 55° C. A chloroform solution of the residue is extracted twice with 0.1 M sodium hydroxide, dried over magnesium sulfate and evaporated to leave the product.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:10].[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1>>[Cl:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([F:9])[C:3]=1[CH2:2][S:18][C:16]1[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=1
Reactant: Fc1cccc(Cl)c1CBr
Reactant: Cc1cc(O)nc(S)n1
Product: Cc1cc(O)nc(SCc2c(F)cccc2Cl)n1
Yield: 82 %

Procedure:
As per procedure from Example 1, 2-(bromomethyl)-1-chloro-3-fluorobenzene and 6-methyl-2-sulfanylpyrimidin-4-ol were reacted together to provide the title compound as a white solid (1.04 g, 82% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 4.53 (s, 2H), 6.01 (bs, 1H), 7.26 (m, 1H), 7.38 (m, 2H); M+282.06.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH2:18](I)[CH3:19]>>[CH2:18]([C:8]1[CH:9]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:11]=[C:3]([C:2]([F:16])([F:17])[F:1])[C:4]=1[C:5]([OH:7])=[O:6])[CH3:19]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CCI
Product: CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O

Procedure:
In analogy to the procedure described for the synthesis of example B.1, the title compound was prepared from 2,4-bis-trifluoromethyl-benzoic acid (commercial) and ethyliodide.
Reaction SMILES: [I:1]Cl.[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[C:16]([Si](C)(C)C)=[CH:17][C:10]=23)[C:6]([C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[N:5]1>C(#N)C>[I:1][C:16]1[N:15]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:11]2=[N:12][CH:13]=[CH:14][C:9]([C:7]3[C:6]([C:31]4[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=4)=[N:5][N:4]([CH3:3])[CH:8]=3)=[C:10]2[CH:17]=1
Reactant: ClI
Reactant: Cn1cc(-c2ccnc3c2cc([Si](C)(C)C)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Solvent: CC#N
Product: Cn1cc(-c2ccnc3c2cc(I)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 53 %

Procedure:
To a solution of ICl (1M in CH2Cl2, 43.3 mmol) in acetonitrile (250 ml) at −10° C. was added a solution of 4-[1-methyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (8.67 mmol) in acetonitrile (46 ml) followed by stirring at −10° C. for 5 minutes. The reaction was concentrated to approx. ⅓ total volume and then diluted with EtOAc (500 ml). The solution was washed with saturated NaHCO3(aq) (100 ml), saturated Na2S2O3(aq) (100 ml), brine (100 ml), and dried over MgSO4. Filtration and concentration in vacuo yielded a tan solid which was triturated with hot acetonitrile/Et2O, providing the title product as a light tan solid (53%). ESMS [M+H]+: 586.0.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:15](=[O:31])[NH:16][C@@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:30])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][C@H:40]1[CH2:46][CH2:45][S:44][C@H:43]2[CH2:47][CH2:48][CH2:49][CH2:50][N:42]2[C:41]1=[O:51]>>[CH2:32]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:39][C@H:40]1[CH2:46][CH2:45][S:44][C@H:43]2[CH2:47][CH2:48][CH2:49][CH2:50][N:42]2[C:41]1=[O:51])=[O:10])[C:15]([NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]1=[O:30])=[O:31])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@@H]1CCCCN(c2ccccc2)C1=O)Cc1ccccc1
Reactant: N[C@H]1CCS[C@H]2CCCCN2C1=O
Product: O=C(N[C@H]1CCCCN(c2ccccc2)C1=O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@H]1CCS[C@H]2CCCCN2C1=O)Cc1ccccc1

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-2-oxo-1-phenylazepan-3-yl)-N6-((4S,10aS)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 24 (20 mg, 0.039 mmol) and Intermediate 40 (10 mg, 0.051 mmol) to give a white solid (16 mg, 58% yield). Anal. Calcd. for C41H50N4O4S m/z 694.4. found: 695.3 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.76 (dd, J=18.7, 7.1 Hz, 2H), 7.35 (t, J=7.8 Hz, 2H), 7.29-7.03 (m, 11H), 5.60 (s, 1H), 5.04-4.85 (m, 1H), 4.76-4.59 (m, 1H), 4.08 (d, J=13.2 Hz, 1H), 3.95 (dd, J=15.3, 11.5 Hz, 1H), 3.52 (d, J=15.9 Hz, 1H), 3.07 (t, J=11.3 Hz, 1H), 2.87-2.35 (m, 11H), 2.08-1.01 (m, 17H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][F:40].O>CS(C)=O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:38][CH2:39][F:40])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: FCCBr
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(NC(COCC1CCN(CCF)CC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Yield: 32.9 %

Procedure:
To a solution of 3-chloro-N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (600 mg, 1.3 mmol) in 6 mL of DMSO was added potassium carbonate (716 mg, 5.2 mmol) and 2-bromo-1-fluoroethane (0.10 mL, 1.1 mmol). The reaction was allowed to stir at room temperature overnight after which time water was added and the resulting precipitate was isolated by filtration. Purification of the filtrate (SiO2: EtOAc) provided 178 mg (28%) of the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:4][CH2:3]1.N1C=CN=C1.[C:41]([Si:45](Cl)([CH3:47])[CH3:46])([CH3:44])([CH3:43])[CH3:42].C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[Si:45]([O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:6][CH2:7]1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:47])[CH3:46]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)c2ccnn12
Reaction time: 2 h

Procedure:
To a solution of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.68 g) and imidazole (0.74 g) in N,N-dimethylformamide (20 mL) was added tert-butyl(chloro)dimethylsilane (1.1 g), and the mixture was stirred for 2 hr. To the reaction mixture were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.89 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([NH:31][C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:6][CH:7]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C=NCc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(NCc1ccccc1)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.4 %

Procedure:
Into a 4 mL vial is added 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (75 mg, 0.289 mmol), anhydrous pyridine (1 mL) and benzyl isocyanate (0.036 mL, 0.289 mmol). The reaction mixture was stirred at r.t. for 2 days. To the reaction mixture is added H2O to precipitate the product. The solid is filtered and purified by preparative TLC (MeOH/CHCl3 10:90) to give a colorless solid (84.3 mg, 75%). m.p. 163-164° C. (dec). 1H NMR (DMSO & CHCl3) 4.23 (d, 2H), 6.05 (t, 1H), 7.05 (m, 1H), 7.08 (m, 4H), 7.25 (t, 3H), 7.42 (d, 2H), 8.02 (s, 1H); ESIMS: m/z 393 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]([NH:29][C@@H:30]([CH2:34][CH2:35][CH2:36][NH:37][C@H:38]2[C:47]3[N:46]=[CH:45][CH:44]=[CH:43][C:42]=3[CH2:41][CH2:40][CH2:39]2)[C:31]([OH:33])=[O:32])=[O:28])=[CH:19][CH:18]=1)C(OC(C)(C)C)=O.[ClH:48].O1CCOCC1>CO>[ClH:48].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]([NH:29][C@@H:30]([CH2:34][CH2:35][CH2:36][NH:37][C@H:38]2[C:47]3[N:46]=[CH:45][CH:44]=[CH:43][C:42]=3[CH2:41][CH2:40][CH2:39]2)[C:31]([OH:33])=[O:32])=[O:28])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)N[C@@H](CCCN[C@@H]2CCCc3cccnc32)C(=O)O)c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(N[C@@H](CCCN[C@@H]1CCCc2cccnc21)C(=O)O)c1ccc(CNCc2ccccn2)c2ccccc12
Reaction time: 2 h

Procedure:
The compound obtained in Example 54-3 (7.2 mg) was dissolved in methanol (0.15 ml) and 4 mol/l hydrochloric acid/dioxane solution (0.15 ml) was added. After 2 hours, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol/water=7/3/0.5). After the addition of 1 mol/l hydrochloric acid, the residue was concentrated and subjected to azeotropic distillation with methanol to obtain hydrochloride of the title compound (6.3 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC#N>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:13]=[CH:12][CH2:11][NH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C=CCNC1

Procedure:
A solution of 5-2 (19.0 g, 63 mmol), Mg(ClO4)2 (2.8 g, 12.7 mmol), and CH3CN was heated at 50° C. for 2 hr. The cooled solution was diluted with CHCl3 and then washed with 1N HCl, sat. NaHCO3, and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 75% EtOAc/hexanes→EtOAc) gave 5-3 as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](Cl)=[O:18])[CH3:13]>CN(C)C(=O)C.C(OCC)C>[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](=[O:9])(=[O:10])[NH2:11])=[O:18])[CH3:13]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CC(=O)Nc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Amino-benzenesulfonamide (5 g, 29 mmol) was dissolved in N,N-dimethylacetamide (25 mL) and diethyl ether (25 mL). Ethyl-3-chloro-3-oxo-propionate (4.6 g, 30.45 mmol) was added into the above reaction solution. The reaction mixture was stirred at 25° C. for 3 h. The product started to precipitate and was collected by vacuum filtration. The solid was dissolved in ethyl acetate (200 mL) and extracted with water (200 mL). The aqueous layer was back-extracted with ethyl acetate (200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, N-(2-sulfamoyl-phenyl)-malonamic acid ethyl ester, as a white solid, which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ: 1.23 (3H, t, J=7.0 Hz), 3.61 (2H, s), 4.14 (2H, quartet, J=7.0 Hz), 7.29-7.33 (1H, m), 7.53 (2H, bs), 7.56-7.60 (1H, m), 7.84-7.86 (1H, m), 7.97-7.99 (1H, m), 9.54 (1H, bs). LC-MS (ESI) calcd for C11H14N2O5S 286.06, found 287.1 [M+H+].
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([C:26]3[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=3)=[N:18][N:17]=2)[CH2:12][CH2:11]1)C(=O)OC(C)(C)C.Cl.C(OCC)C>ClCCl>[CH3:1][NH:2][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([C:26]3[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=3)=[N:18][N:17]=2)[CH2:12][CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(-c3ccnn3C)c3ccccc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CNC1CCN(c2nnc(-c3ccnn3C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
Dissolve tert-butyl methyl(1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)carbamate (7.77 g, 18.39 mmol) in dichloromethane (100 mL). Add an excess of 1 M hydrogen chloride in diethyl ether (20 mL, 80 mmol) to the solution and stir at ambient temperature for 2 h. Concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (dichloromethane:2 M NH3 in MeOH=10:1) to provide the title compound as a yellow foam (5.83 g, 98%). ES/MS m/z 323.2 (M+1).
Reaction SMILES: [C:1]([NH:20][CH2:21][C:22]1[O:23][CH2:24][CH2:25][CH2:26][CH:27]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:28].[Na+].OO>O1CCCC1>[C:1]([NH:20][CH2:21][CH:22]1[CH:27]([OH:28])[CH2:26][CH2:25][CH2:24][O:23]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: C1=C(CNC(c2ccccc2)(c2ccccc2)c2ccccc2)OCCC1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1CCCOC1CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.6 %

Procedure:
A solution of a borane-tetrahydrofuran complex in tetrahydrofuran (1 M, 187 mL, 187 mmol) was added dropwise to a solution of 2-(tritylamino)methyl-5,6-dihydro-4H-pyran (22.2 g, 62.4 mmol) in tetrahydrofuran (180 mL) at room temperature over 20 minutes. After stirring at room temperature for 2.5 hours, the reaction solution was ice-cooled, and a 3N sodium hydroxide solution (208 mL, 624 mmol) was added dropwise over 10 minutes. Subsequently a 31% hydrogen peroxide solution (69 mL, 629 mmol) was added dropwise at the same temperature over 10 minutes, and then the mixture was stirred at room temperature for one hour. The reaction solution was extracted with diethyl ether (2×300 mL). The combined organic layers were washed with water (300 mL) and brine (300 mL), and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and then the residue was suspended in a mixed solvent of dichloromethane/hexane (1:1, 80 mL). The insoluble material was removed by filtration, and then the filtrate was evaporated under reduced pressure to give 18.54 g (80%) of the title compound as a pale yellow gummy solid.
Reaction SMILES: [CH:1](Br)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:21](#[N:23])[CH3:22]>O>[CH:1]([N:23]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:22]=[CH:21]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: c1ccc(C(c2ccccc2)n2ccc3ccccc32)cc1
Temperature: 25 °C
Yield: 45 %

Procedure:
(Step 4, 1 eq), Ph2CHBr (1.5 eq) and Cs2CO3 (1.5 eq) were mixed in dry acetonitrile (0.1M). The mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic phase was concentrated and the residue was chromatographed with CH2Cl2 as eluent to give the N-benzhydryl indole as an orange gum in 45% yield. m/z (M+H)+ 701.3
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[CH2:16](O)[CH2:17][OH:18].O>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:15]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[C:5]1([C:8]#[N:9])[CH2:6][CH2:7][C:2]2([O:18][CH2:17][CH2:16][O:1]2)[CH2:3][CH2:4]1
Reactant: N#CC1(c2ncccn2)CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: N#CC1(c2ncccn2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of 4-oxo-1-(pyrimidin-2-yl)cyclohexanecarbonitrile (333 mg, 1.66 mmol), ethylene glycol (96.9 μl, 1.74 mmol), and p-toluenesulfonic acid monohydrate (15.7 mg, 82.7 μmol) in benzene (10 mL) was refluxed for 1.5 h while the water formed during the reaction was removed azeotropically using a Dean-Stark apparatus. After being cooled down to room temperature, the reaction was diluted (Et2O) and washed (2×H2O, 2×sat aqueous NaHCO3, and 2× brine). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, 40-50% EtOAc/Hexanes, gradient elution) gave 8-pyrimidin-2-yl-1,4-dioxa-spiro[4,5]decane-8-carbonitrile (325 mg, 1.33 mmol, 80%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[C:11]([C:13]([C:19]#[N:20])=[C:14](SC)[NH:15][CH3:16])#[N:12]>>[C:11]([C:13]([C:19]#[N:20])=[C:14]([NH:15][CH3:16])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)#[N:12]
Reactant: CNC(SC)=C(C#N)C#N
Reactant: NCCSCc1nccs1
Product: CNC(NCCSCc1nccs1)=C(C#N)C#N

Procedure:
By the procedure of Example 1(ii), reacting 2-[(2-aminoethyl)-thiomethyl]thiazole with 1,1-dicyano-2-methylthio-2-methylaminoethylene gives the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:28](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[CH3:28])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Br)cc(N(C)C2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 80 °C
Yield: 71.6 %

Procedure:
To a stirred solution of methyl 5-bromo-3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-2-methylbenzoate (1.5 g, 4.6 mmol) in acetonitrile (15 mL) was added cesium carbonate (2.63 g, 8.1 mmol) and methyl iodide (2.86 g, 20.32 mmol). The mixture was heated at 80° C. for 7 h. On completion, the reaction was cooled to room temperature, filtered, and the residue was washed with ethyl acetate. The filtrate was concentrated to afford methyl 5-bromo-3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)(methyl)amino)-2-methylbenzoate (1.5 g).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][N:7]1[C:13](=[O:14])[CH2:12][C:11]2[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:10]=2[CH:9]=[CH:8]1)C>S(=O)(=O)(O)O.C(O)C>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:11]2[CH2:12][C:13](=[O:14])[N:7]([CH2:6][CH2:5][CH:4]=[O:3])[CH:8]=[CH:9][C:10]=2[CH:18]=1
Reactant: CCOC(CCN1C=Cc2cc(OC)c(OC)cc2CC1=O)OCC
Agent: O=S(=O)(O)O
Solvent: CCO
Product: COc1cc2c(cc1OC)CC(=O)N(CCC=O)C=C2
Temperature: 40 °C

Procedure:
Here, 3-(7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-propionaldehyde diethylacetal (3.5 g, 0.01 mol) is heated to 40° C. for 2 hours in 2N sulphuric acid (50 ml) and ethanol (50 ml). The alcohol is distilled off in vacuo, the residue is made alkaline with saturated potassium carbonate solution while cooling and extracted several times with ethyl acetate. The ethyl acetate extract is extracted twice with 5% sodium hydrogen sulfate solution. The bisulphate extract is acidified with concentrated hydrochloric acid and heated to 40° C. in vacuo for half an hour to eliminate the sulphur dioxide. Then saturated potassium carbonate solution is added, the mixture is extracted several times with methylene chloride, dried over magnesium sulphate and concentrated by evaporation.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([N:10]3[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]3)=[C:8]([N+:24]([O-])=O)[CH:7]=[N:6]2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([NH:34][C:35]1[S:39][C:38]([C:40]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=2[F:47])=[N:37][C:36]=1[C:48](O)=[O:49])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[F:47][C:41]1[CH:42]=[CH:43][CH:44]=[C:45]([F:46])[C:40]=1[C:38]1[S:39][C:35]([NH:34][C:32](=[O:33])[O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[C:36]([C:48](=[O:49])[NH:24][C:8]2[CH:7]=[N:6][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:9]=2[N:10]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]2)[N:37]=1
Reactant: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2CC2CC2)CC1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnn(CC2CC2)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 77 %

Procedure:
(R)—N-(1-(1-cyclopropylmethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid were reacted to give (R)-tert-butyl 2-(2,6-difluorophenyl)-4-(1-cyclopropylmethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (136 mg, 77%). 1H-NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 8.75 (s, 1H), 7.95 (s, 1H), 7.41-7.36 (m, 1H), 7.10-7.02 (m, 2H), 6.37 (d, J=8 Hz, 1H), 4.25-4.10 (m, 1H), 3.90-3.83 (m, 2H), 3.43-3.31 (m, 2H), 3.30-3.15 (m, 2H), 2.25-2.05 (m, 2H), 2.03-1.70 (m, 4H), 1.57 (s, 9H) 1.35-1.20 (m, 1H), 0.64-0.59 (m, 2H), 0.43-0.38 (m, 2H).