Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10]([C:18]4[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=4)=[C:11]4[C:16](=[CH:17][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4.S(Cl)([Cl:32])(=O)=O.O>C(Cl)(Cl)Cl>[Cl:32][C:17]1[C:7]2[S:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:9]=3[C:8]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=2)=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2
Reactant: CS(=O)(=O)Oc1ccc(-c2c3ccccc3cc3sc4ccccc4c23)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CS(=O)(=O)Oc1ccc(-c2c3ccccc3c(Cl)c3sc4ccccc4c23)cc1
Reaction time: 19 h
Yield: 88.3 %

Procedure:
To a solution of methanesulfonic acid 4-benzo[b]naphtho[2,3-d]thiophen-11-yl-phenyl ester (1.00 g, 2.47 mmol) in chloroform (10 mL) was added sulfuryl chloride (0.21 mL, 2.60 mmol, 1.05 eq) dropwise at room temperature under a dry nitrogen atmosphere. After stirring 19 hours the reaction mixture was added to water (100 mL) and the organics were extracted with ether (2×100 mL). The extracts were combined, washed with brine, combined with silica gel and the solvent was removed. The adsorbate was flash chromatrographed (85/15 petroleum ether/ethyl acetate) to give the title compound as a white solid (0.957 g, 88%): mp 155-158° C.; NMR (CDCl3); δ 8.41 (ddd, J=8, 1, 1 Hz, 1H), 7.82 (ddd, J=8, 1, 1 Hz, 1H), 7.67 (ddd, J=8, 7, 1 Hz, 1H), 7.61-7.56 (m, 3H), 7.51-7.45 (m, 3H), 7.42-7.38 (ddd, J=8, 7, 1 Hz, 1H), 7.10 (ddd, J=8, 7, 1 Hz, 1H), 6.64 (d, J=8 Hz, 1H), 3.34 (s, 3H); MS (+EI) : [M+], 1 chlorine isotope pattern, 438 (100%), 440 (40%); Anal. Calc. for C23H15ClO3S2: C, 62.93, H, 3.49, N, 0.00. Found: C, 62.72, H, 3.25, N, 0.03.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[P:7]([OH:10])([OH:9])[OH:8]>CC(C)=O>[NH2:2][C:1]([P:7]([OH:10])([OH:9])=[O:8])([P:7]([OH:10])([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: N#CCC(=O)O
Reactant: OP(O)O
Solvent: CC(C)=O
Product: NC(CC(=O)O)(P(=O)(O)O)P(=O)(O)O
Temperature: 165 °C

Procedure:
A mixture of cyanoacetic acid (4.3 g, 0.5 mole), phosphorous acid (8.2 g, 0.1 mole), ISOPAR-M (20 g), and the wetting agents (0.25 g each) was heated at 165° C for 2 hours. The product was worked up with acetone to get yellow crystals of 1-amino-1,1-diphosphono-2-carboxy ethane, m.p. 255° C (decomposition), 55%, associated with traces of impurities.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][CH2:21][CH:20]([NH2:24])[CH2:19]3)[C:15]2=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][CH2:21][CH:20]([NH:24][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=4)[CH2:19]3)[C:15]2=[O:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC3(CCCC(N)C3)C2=O)CC1
Reactant: O=C(O)c1cccc(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N2CCC3(CCCC(NC(=O)c4cccc(F)c4)C3)C2=O)CC1

Procedure:
4-(7-Amino-1-oxo-2-aza-spiro[4.5]dec-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.57 mmol), 3-fluorobenzoic acid (0.080 g, 0.56 mmol), BOP (0.252 g, 0.57 mmol), and triethylamine (0.115 g, 1.14 mmol) in methylene chloride (5.0 mL) was stirred at rt overnight. The mixture was concentrated, and the resulting residue was purified with chromatography (ethyl acetate) to afford the title compound which is a mixture of two diastereomers (cis/trans: 3/2; under LC-MS method C, the first peak with RT of 1.47 min was assigned as cis, and the second peak with RT of 1.50 min was assigned as trans.). 1H NMR (400 MHz, CDCl3) δ 8.5 (s, 0.6 H), 7.60-7.68 (m, 1H), 7.36-7.50 (m, 2H), 7.14-7.20 (m, 1H), 5.92 (d, J=6.8 Hz, 0.4 H), 4.55-4.65 (m, 0.4 H), 4.04-4.38 (m, 3.6H), 3.20-3.30 (m, 2H), 2.71-2.86 (m, 2H), 1.28-2.25 (m, 23H). ESI-MS m/z: 474 (M+H)+.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].Cl[CH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1>CN(C)C=O>[S:32]1[CH:33]=[CH:34][N:35]=[C:31]1[CH2:30][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:15]2[CH:14]=[C:13]([C:12]3[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=3)[O:17][N:16]=2)=[CH:20][CH:21]=1
Reactant: ClCc1nccs1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4nccs4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (50 mg, 0.18 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (35.4 μL, 0.18 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a suspension of this solid in N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-thiazole (28.4 mg, 0.21 mmol) described in manufacturing Example 88-1-2, which was stirred for 3 hours at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (43.0 mg, 64%).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[F:24][C:25]([F:34])([F:33])[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]([F:24])([F:33])[F:34])=[CH:27][CH:28]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(Br)c1ccc(OCCOc2ccc(Cl)cc2)cc1
Product: COC(=O)C(Oc1ccc(C(F)(F)F)cc1)c1ccc(OCCOc2ccc(Cl)cc2)cc1

Procedure:
As described in Example 44, 8.0 g of methyl bromo{p-[2-(p-chlorophenoxy)ethoxy]phenyl}acetate is reacted with p-trifluoromethylphenol to give 7.4 g of product as white crystals. Recrystallization from methanol gives white crystals, mp 95°-97° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cccc1F
Reactant: CN1CCNCC1
Product: CN1CCN(c2cccc(F)c2C#N)CC1

Procedure:
2,6-Difluorobenzonitrile is reacted with N-methyl piperazine following the procedure of Example 5. The reaction mixture is extracted with methylene chloride after addition of water. The methylene chloride is extracted with dilute HCl which is basified and extracted with methylene chloride. The resulting crude oil after evaporation is taken in ethanol and i-PrOH-HCl is added to give the title compound as the hydrochloride salt, 1.4 g m.p. 245°-247° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:21]1([CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)CCCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCc1ccccc1)NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A suspension of 0.32 mmol rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) in 5 ml acetonitrile was treated successively with 0.32 mmol 4-phenylbutyric acid, 1.61 mmol DIPEA and 0.35 mmol TBTU. The reaction mixture was stirred for 1 hour at room temperature and concentrated. Chromatography (SiO2; dichloromethane/methanol) gave the title compound as a colorless solid. Yield=71%. MS (m/e): 419.3 (MH−, 100%).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:35]([NH:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[C:27]([O:26][CH3:25])=[O:37])=[O:36])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added methyl-2-isocyanatobenzoate (216 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 239 mg (69.5%) of the desired product as a solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]3)=[C:16]([NH2:29])[CH:15]=2)=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]3)=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3c[nH]c4ccccc34)n2)c(OC)cc1N1CC(N(C)C)C1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of acryloyl chloride (0.057 mL, 0.70 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of N-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine (Intermediate 118, 310 mg, 0.67 mmol) and DIPEA (0.127 mL, 0.73 mmol) in CH2Cl2 (40 mL), which was cooled in an ice/water bath to 0° C. The mixture was stirred while in the ice/water bath for 1 h and was then allowed to warm to r.t. The mixture was then held at r.t. for 18 h, and was then diluted with CH2Cl2 (100 mL). This solution was then washed with sat. NaHCO3 (200 mL) and the aqueous wash solution was extracted with CH2Cl2 (2×100 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound together with an impurity (172 mg, 50%) as a pale yellow solid. 120 mg of this material was purified by crystallisation from CH3CN to give the title compound (85 mg, 0.164 mmol) as a yellow solid without evidence of the impurity by NMR analysis. The mother liquors from the crystallization and a further impure fraction from the FCC (containing a 75:25 mixture of product:starting material) were combined, concentrated in vacuo and was purified by crystallisation from CH3CN to give more of the title compound (40 mg, 12%) as a tan solid; 1H NMR: 2.09 (6H, s), 3.03-3.12 (1H, m), 3.58 (2H, t), 3.78 (3H, s), 3.96 (2H, t), 5.66 (1H, dd), 6.16 (1H, dd), 6.25 (1H, s), 6.46 (1H, dd), 7.07 (1H, t), 7.16 (1H, t), 7.45 (1H, d), 7.48 (1H, s), 8.24 (1H, s), 8.27-8.31 (1H, br s), 8.31 (1H, s), 8.46 (1H, d), 9.22 (1H, s), 11.79 (1H, s); m/z: ES+ MH+ 518.23.
Reaction SMILES: [NH2:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[CH:8](=[N:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: Nn1nnnc1S
Solvent: CCO
Product: Sc1nnnn1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 689.4 %

Procedure:
7.0 g of 1-amino-5-mercapto-1H-tetrazole and 0.6 g of benzaldehyde were dissolved in 120 ml of ethanol, and the solution was stirred at room temperature for 4 hours. After the reaction, the solution was evaporated to remove solvent. The residue was dissolved in 50 ml of ethyl acetate. The ethyl acetate solution was washed with water, dried and evaporated to remove solvent. Then, isopropyl ether was added to the residue obtained, and the crystalline precipitates were collected by filtration. 8.0 g of 1-benzylideneamino-5-mercapto-1H-tetrazole were obtained as colorless needles. mp 119°-120° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](=[O:9])O[CH:8]=1.C1(=O)[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]1>ClC1C=CC=CC=1Cl>[F:10][C:2]([F:1])([F:11])[C:3]1[CH:4]=[C:5]2[C:14](=[CH:13][CH:8]=1)[C:15](=[O:18])[CH:16]=[CH:17][C:6]2=[O:9]
Reactant: O=c1ccc(C(F)(F)F)co1
Reactant: O=C1C=CC(=O)C=C1
Solvent: Clc1ccccc1Cl
Product: O=C1C=CC(=O)c2cc(C(F)(F)F)ccc21

Procedure:
1.64 g (0.01 mol) of 5-trifluoromethyl-2-oxo-2H-pyran and 5.4 g (0.05 mol) of 1,4-benzoquinone in 7 ml of 1,2-dichlorobenzene are heated at 180° C. for 12 hours. The reaction mixture is then evaporated at 90°/20 mbar, and the distillation residue is chromatographed on 150 g of silica gel 60 (eluent CH2Cl2 : acetone 19:1; excess pressure of 0.3 bar), yield 1.82 g (80.53%); m.p. 80°-85°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:33])[CH2:10][C@@:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH:39]=O.C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:33])[CH2:10][C@@:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([CH2:39][C:35]2[S:34][CH:38]=[CH:37][CH:36]=2)[CH2:13][CH2:12]1
Reactant: O=Cc1cccs1
Reactant: CCc1ccc(-c2ccc([C@@]3(CC(=O)NOC4CCCCO4)CCNCCS3(=O)=O)s2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1ccc(-c2ccc([C@@]3(CC(=O)NOC4CCCCO4)CCN(Cc4cccs4)CCS3(=O)=O)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
To a solution of N-(2-tetrahydropyranyloxy)-2-[(S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (70.0 mg) and 2-thiophenecarbaldehyde (19.1 mg) in ethanol (1 ml) was added sodium cyanoborohydride (10.7 mg) and a drop of acetic acid at 0° C. The resulting mixture was stirred for 3 hours at room temperature. The reaction was quenched by the addition of saturated sodium bicarbonate (1 ml), and the solvent was evaporated off. The residue was dissolved in ethyl acetate (20 ml), and washed with water, brine, dried over magnesium sulfate, and evaporated. Silica gel column chromatography [eluent: acetone/chloroform (10:1)] afforded N-(2-tetrahydropyranyloxy)-2-[(S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-4-(2-thienylmethyl)-1,4-thiazepin-7-yl]acetamide (74.4 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[CH2:2][CH:3]=[CH2:4].[CH3:12][SiH:13]([CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH3:14]>>[Cl:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH2:4][Si:13]([CH3:14])([CH3:12])[CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][CH:9]=1
Reactant: C=CCCc1ccc(Cl)cc1
Reactant: C[SiH](C)C[Si](C)(C)C
Product: C[Si](C)(C)C[Si](C)(C)CCCCc1ccc(Cl)cc1
Yield: 70.8 %

Procedure:
About 33.3 g (0.2 mol) of 4-(3-butenyl)-1-chlorobenzene prepared in accordance with Example 1 (b) were silylated with 2,4,4-trimethyl-2,4-disilapentane (compare Example 1 (d) with Pt as catalyst to give 1-chloro-4-(5,5,7,7-tetramethyl-5,7disilaoctyl)benzene. The boiling point was 115° C. under 0.05 hPa, and the yield was 70.8% of theory.
Reaction SMILES: C([C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:24]=[N:23][C:22]=1OC)(C)C.[OH-:35].[Na+]>C(O)C>[CH2:8]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:21]1[C:22](=[O:35])[NH:23][N:24]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[CH:26]=1)[CH:9]([CH3:13])[CH3:10]
Reactant: COc1nnc(-c2ccncc2)cc1-c1[nH]c2cc(CN3CCN(C)CC3)ccc2c1C(C)C
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Cc1c(-c2cc(-c3ccncc3)n[nH]c2=O)[nH]c2cc(CN3CCN(C)CC3)ccc12
Temperature: 150 °C
Yield: 41 %

Procedure:
98 mg 3-Isopropyl-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-6-(4-methyl-piperazin-1-ylmethyl)-1H-indole are dissolved in 1.23 mL ethanol. 1.18 mL 1 N aqueous sodium hydroxide are added. The reaction mixture is heated to 150° C. in a microwave oven for 15 minutes. Purification by HPLC affords 39 mg (41%) 4-[3-isobutyl-6-(4-methyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-6-pyridin-4-yl-2H-pyridazin-3-one as its trifluoroacetate salt.
Reaction SMILES: [C:1]([C:4]([F:23])=[C:5]1[CH:12]2[CH2:13][C:8]3([O:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2)(O)=[O:2].[Br:24][C:25]1[C:26]([S:32]([NH2:35])(=[O:34])=[O:33])=[C:27]([Cl:31])[S:28][C:29]=1[Cl:30]>>[Br:24][C:25]1[C:26]([S:32]([NH:35][C:1](=[O:2])[C:4](=[C:5]2[CH:12]3[CH2:13][C:8]4([O:15][C:16](=[O:22])[CH2:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:9][CH:10]([CH2:14][CH:6]2[CH2:7]4)[CH2:11]3)[F:23])(=[O:33])=[O:34])=[C:27]([Cl:31])[S:28][C:29]=1[Cl:30]
Reactant: NS(=O)(=O)c1c(Cl)sc(Cl)c1Br
Reactant: CC(C)(C)CC(=O)OC12CC3CC(C1)C(=C(F)C(=O)O)C(C3)C2
Product: CC(C)(C)CC(=O)OC12CC3CC(C1)C(=C(F)C(=O)NS(=O)(=O)c1c(Cl)sc(Cl)c1Br)C(C3)C2

Procedure:
Coupling of 3,3-dimethyl-butyric acid 4-(carboxy-fluoro-methylene)-adamantan-1-yl ester with 4-bromo-2,5-dichloro-thiophene-3-sulfonamide and isolation is performed analogously to the method as described in Example K c. 3,3-Dimethyl-butyric acid 4-[2-(4-bromo-2,5-dichloro-thiophene-3-sulfonylamino)-1-fluoro-2-oxo-ethylidene]-adamantan-1-yl ester is obtained.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH3:23])[C:6](=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Cl)[N:15]=1)#[N:2].[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[N:34]([CH3:35])[C:33](=[O:36])[CH2:32][CH2:31][CH2:30][C:29]=2[CH:37]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>C(O)(C)C>[Cl:20][C:19]1[C:14]([NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([N:5]([CH2:4][CH2:3][C:1]#[N:2])[CH3:23])=[O:22])=[N:15][C:16]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[N:34]([CH3:35])[C:33](=[O:36])[CH2:32][CH2:31][CH2:30][C:29]=3[CH:37]=2)=[N:17][CH:18]=1
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Reactant: CN(CCC#N)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CN(CCC#N)C(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Cl
Yield: 34.9 %

Procedure:
N-(2-Cyano-ethyl)-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (101 mg, 0.288 mmol), 7-Amino-1-methyl-1,3,4,5-tetrahydro-1-benzazepin-2-one (48 mg, 0.25 mmol), and 10-Camphorsulfonic acid (5.0 mg, 0.022 mmol) in Isopropyl alcohol (2.0 mL) were added into a microwave vial and irradiated at 120° C. for 30 min. The reaction was diluted with satd. sodium bicarbonate (5 mL) and cooled to aid in precipitate formation. The solids were collected and washed with 7 mL water. The solids contained product with starting chloropyrimidine and another impurity. The filtrate contained the aniline component, product and other impurities. The filtrate was extracted 3×10 mL DCM, dried and concentrated. The solids were chromatographed (ISCO, 12 g silica gel, 0-100% EtOAc:Hex) separately from the filtrate, and clean fractions were combined to give the product as a yellow foam (44 mg, 35%). LCMS: 504 (M+H), 1H-NMR (CDCl3): 8.93 (s, 1H), 8.34 (d, 1H, J=8.2 Hz), 8.10 (s, 1H), 7.44 (m, 3H), 7.37 (d, 1H, J=7.8 Hz), 7.18 (dd, 1H, J=7.4, 7.4 Hz), 7.07 (d, 1H, J=8.3 Hz), 6.95 (s, 1H), 3.81 (br s, 2H), 3.33 (s, 3H), 3.20 (s, 3H), 2.81 (br s, 2H), 2.64 (m, 2H), 2.32 (t, 2H, J=7.2 Hz), 2.15 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][CH2:6]1)=O.[C:15]([O:19][C:20](=[O:35])[CH2:21][CH2:22][N:23]([CH2:27][C:28]1[S:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=1)[C:24]([NH2:26])=[S:25])([CH3:18])([CH3:17])[CH3:16]>CO>[C:15]([O:19][C:20](=[O:35])[CH2:21][CH2:22][N:23]([C:24]1[S:25][CH:2]=[C:3]([C@H:5]2[CH2:10][CH2:9][C@H:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][CH2:6]2)[N:26]=1)[CH2:27][C:28]1[S:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)[C@H]1CC[C@H](C(=O)CBr)CC1
Reactant: CCc1ccc(CN(CCC(=O)OC(C)(C)C)C(N)=S)s1
Solvent: CO
Product: CCc1ccc(CN(CCC(=O)OC(C)(C)C)c2nc([C@H]3CC[C@H](C(C)(C)C)CC3)cs2)s1

Procedure:
2-Bromo-1-(trans-4-tert-butyl-cyclohexyl)-ethanone (72 mg, 0.277 mmol) was added to a methanol (about 4 mL) solution of 3-[1-(5-ethyl-thiophen-2-ylmethyl)-thioureido]-propionic acid tert-butyl ester (100 mg, 0.304 mmol) to obtain 3-[[4-(trans-4-tert-butyl-cyclohexyl)-thiazol-2-yl]-(5-ethyl-thiophen-2-ylmethyl)-amino]-propionic acid tert-butyl ester (108 mg, 0.220 mmol) following a method analogous to General Procedure C (and similar to the procedure found in Example 5). Hydrolysis of this ester following a method analogous to General Procedure G1 using 1 N NaOH (aq) solution (2 mL), THF (1 mL) and MeOH (1 mL) gave 3-[[4-(trans-4-tert-butyl-cyclohexyl)-thiazol-2-yl]-(5-ethyl-thiophen-2-ylmethyl)-amino]-propionic acid (37 mg, 0.085 mmol). LC-MS m/z: 435 (M+1)+.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH:38]([CH3:40])[CH3:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH2:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])[CH:38]([CH3:40])[CH3:39]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)CNS(=O)(=O)c1cccc(N)c1
Product: CC(C)CNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-isobutyl-benzenesulfonamide [CAS 608523-95-1] according to general procedure II. Yellow solid. MS (ISP) 566.2 [(M−H)−]; mp 186° C.