Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=1.[C:15]([O:22][CH3:23])(=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:20][O:19][C:17](=[O:18])[CH:16]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:6][C:5]([O:4][CH3:3])=[O:14])[CH:12]=1)[C:15]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CC(=O)OC
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(C(C(=O)OC)C(=O)OC)c1
Yield: 44.3 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (0.104 g, 0.113 mmol), tri-(tert-butyl)phosphonium tetrafluoroborate (65.8 mg, 0.227 mmol) and sodium hydride (295 mg, 60% dispersion in mineral oil) were charged into a flask under an argon atmosphere. (3-Bromophenyl)acetic acid methyl ester (1.30 g, 5.67 mmol) was dissolved in THF (10 ml) and added to the mixture. Subsequently, dimethyl malonate (0.995 g, 7.37 mmol) was added and the mixture stirred under reflux overnight. The mixture was filtered over a small plug of silica gel, evaporated to dryness and the residue purified by silica gel chromatography (HEP/EA gradient) to yield 0.704 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]2[NH:30][N:29]=[N:28][N:27]=2)[CH:23]=[CH:24][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH:21]=3)(=[O:17])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cccc(S(=O)(=O)Cl)c2)cc1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: COc1ccc(-c2cccc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)c2)cc1
Yield: 58.9 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from [3-(4-methoxyphenyl)phenyl]sulfonyl chloride (16 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) giving 12 mg (60%) of the title compound. MS (ESI+) calcd for C20H17N5O3S 407.10521, found 407.10532.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=O)[CH2:4][C:5](=O)[CH3:6].[Cl:11][C:12]1[CH:27]=[CH:26][C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[N:24]=[C:23]([NH2:25])[NH:22][N:21]=2)=[CH:14][CH:13]=1>C(O)(=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[N:24]=[C:23]3[N:25]=[C:5]([CH3:6])[CH:4]=[C:3]([C:2]([F:10])([F:9])[F:1])[N:22]3[N:21]=2)=[CH:26][CH:27]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1nc(CCCOc2ccc(Cl)cc2)n[nH]1
Solvent: CC(=O)O
Product: Cc1cc(C(F)(F)F)n2nc(CCCOc3ccc(Cl)cc3)nc2n1
Temperature: 135 °C
Reaction time: 15 h
Yield: 41.8 %

Procedure:
A mixture of 1,1,1-trifluoro-2,4-pentanedione (91 mg, 0.594 mmol), 3-[3-(4-chlorophenoxy)propyl]-1H-1,2,4-triazol-5-amine (150 mg, 0.594 mmol), and glacial acetic acid (2.0 mL) was added to a 50 mL RBF with a magnetic stirring bar. The flask was fitted with a condenser, and warmed in an oil bath to a gentle reflux at 135° C. Progress of the reaction was monitored by analytical HPLC with UV detection at 215 nm. The starting material elutes with retention time of 5.1 min, and the product elutes with retention time of 6.89 min. After 15 h, the solution was allowed to cool to room temperature and added to stirring ice/water (17 mL). Solid material was isolated by filtration, rinsed with 15 mL of water, and then dried under reduced pressure. The solid was dissolved in ethanol (3 mL) and water (1 mL) with gentle warming and allowed to cool. The needles that formed were isolated by filtration, washed with 3 mL of cold ethanol, and allowed to dry to afford the title compound (92 mg, 41% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.83 (s, 1H), 7.31 (d, 2H), 6.95 (d, 2H), 4.09 (t, 2H), 3.03 (t, 2H), 2.70 (s, 3H), 2.21 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[F:12].OS(O)(=O)=O.[CH3:18]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:18])=[O:10])=[CH:4][C:3]=1[F:12]
Reactant: CO
Reactant: O=C(O)Cc1ccc(Cl)c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(Cl)c(F)c1
Yield: 99.8 %

Procedure:
A solution of 2-(4-chloro-3-fluorophenyl)acetic acid (10.07 g, 53.4 mmol) and concentrated H2SO4 (0.297 mL, 5.34 mmol) in MeOH (200 mL, 4940 mmol) was stirred at 95° C. for 17 hours in a 350 mL sealed vessel. The solution was concentrated in vacuo and then made basic with 1N NaOH(aq) (100 mL). The resulting mixture was extracted with EtOAc (2×100 mL), washed with water (100 mL), and then washed with brine (75 mL). The combined organic layers were dried over MgSO4, concentrated, and dried in vacuo to give methyl 2-(4-chloro-3-fluorophenyl)acetate (10.80 g). MS m/e=203.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40]O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][O:32][CH3:31])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Reactant: COCCOCCOCCO
Product: COCCOCCOCCOC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Yield: 74 %

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and 2-(2-(2-methoxyethoxy)ethoxy)ethanol according to Method E (yellow solid, 199 mg, 0.352 mmol, 74% yield). ES-HRMS m/z calc. for C31H36ClN3NaO5 (M+Na) 588.2241, found 588.2245.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccnc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
A mixture of 0.64 g of 2-fluoro-4-pyridinemethanol, 10 ml of chloroform and 2.54 g of Dess-Martin Periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one) was stirred for 30 minutes at room temperature. A saturated sodium hydrogen carbonate aqueous solution was poured, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.19 g of 2-fluoropyridine-4-carbaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[C:22]2[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=2[C:20]2[C:19]3[CH:18]=[C:17]([O:28]C)[CH:16]=[CH:15][C:14]=3[N:13]([CH2:30][CH2:31][OH:32])[C:12]=2[CH:11]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[C:22]2[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=2[C:20]2[C:19]3[CH:18]=[C:17]([OH:28])[CH:16]=[CH:15][C:14]=3[N:13]([CH2:30][CH2:31][OH:32])[C:12]=2[CH:11]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4c(Cl)cccc4OC)cc1n2CCO)C(=O)NC3=O
Agent: BrB(Br)Br
Product: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCO
Reaction time: 2 h
Yield: 56 %

Procedure:
The reaction of 4-(2-Chloro-6-methoxyphenyl)-6-(2-hydroxyethyl)-9-methoxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (V; Ar=2-chloro-6-methoxyphenyl, R10═CH2CH2OH) (111) prepared as described in example 63 with BBr3 using the procedure described in example 80 except that the reaction conditions were 2 h at 0° C. gave 4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-(2-hydroxyethyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (VI; Ar-2-chloro-6-methoxyphenyl, R10═CH2CH2OH) (112) in a 56% yield as a yellow powder (56%); mp 275–278° C. 1H NMR δ [(CD3)2SO] 10.98 (br s, 1H). 9.30 (br s, 1H), 8.36 (d, J=2.4 Hz, 1H), 7.70 (s, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.43 (dd, J=8.3, 8.3 Hz, 1H), 7.17 (d, J=7.9 Hz, 1H), 7.14–7.09 (m, 2H), 4.81 (t, J=5.5 Hz, 1H), 4.46 (t, J=5.3 Hz, 2H), 3.74 (dt, J=5.5, 5.3 Hz, 2H), 3.66 (s, 3H). FABMS found [M+H]+: 439.0882, 437.0889. C23H18ClNO5 requires 439.0875, 437.0904.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([N:18]2C(=O)C3C(=CC=CC=3)C2=O)[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=1[O:11][CH3:12])=[O:5])[CH3:2].NN>CCO>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=1[O:11][CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(N2C(=O)c3ccccc3C2=O)c(C(=O)OCC)c1OC
Agent: NN
Solvent: CCO
Product: CCOC(=O)c1cn(N)c(C(=O)OCC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
A mixture of 393D (0.58 g, 1.58 mmol) and NH2NH2 (60 μl, 2.21 mmol) in EtOH (5 ml) was stirred at rt overnight, filtered through Celite, the filtrate was concentrated and the residue was purified by silica gel flash column chromatography to give 393E (0.30 g, 75%) (0%-5% EtOAc—CH2Cl2).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:6][C:5]=1[S:21]([F:26])([F:25])([F:24])([F:23])[F:22])([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:6][C:5]=1[S:21]([F:26])([F:25])([F:22])([F:23])[F:24]
Reactant: O=C1c2ccccc2C(=O)N1c1ccc([N+](=O)[O-])c(S(F)(F)(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2C(=O)c3ccccc3C2=O)cc1S(F)(F)(F)(F)F

Procedure:
1.94 g (4.92 mmol) of 2-(4-nitro-3-pentafluorosulfanylphenyl)isoindole-1,3-dione (prepared in example 4) were dissolved in 20 ml of methanol, admixed with 10% palladium on activated carbon and hydrogenated at room temperature at a hydrogen pressure of 5 bar. On completion of reaction, the catalyst was filtered off and the filtrate concentrated. The residue was stirred in a mixture of dichloromethane and n-heptane, filtered with suction and dried under reduced pressure. 2-(4-amino-3-pentafluorosulfanylphenyl)isoindole-1,3-dione having a melting point of 176-178° C. was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:11].[Cl:12][C:13]1=[C:14]([Cl:20])[C:15]([O:17][C:18]1=[O:19])=[O:16]>C(Cl)CCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:15](=[O:16])[C:14]([Cl:20])=[C:13]([Cl:12])[C:18]([OH:19])=[O:17])=[C:3]1[CH3:11]
Reactant: Cc1cc2ccccc2n1C
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: ClCCCl
Product: Cc1c(C(=O)C(Cl)=C(Cl)C(=O)O)c2ccccc2n1C
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A mixture of 10.0 g (0.07 mole) of 1,2-dimethylindole, 12.0 g (0.07 mole) of dichloromaleic anhydride and 200 ml of ethylene dichloride was stirred at ambient temperature for approximately eighteen hours. The solid present in the reaction mixture was collected by filtration. After drying at 60° C. in vacuo there was obtained 20.0 g of 4-(1,2-dimethyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid (Formula VIII: R=R1 =CH3 ; Y=H) as a pale blue solid which melted over the range 150° to 153° C. Infrared spectral analysis showed a maximum at 1712 (C=O; s) cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2c(-c3ccc(Cl)cc3)nn(-c3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.3 mmol) in CH2Cl2 (5 mL) was treated with phenylboronic acid (0.6 mmol), pyridine (0.6 mmol), and copper(II) acetate (4.5 mmol). The mixture was stirred at RT for 16 h. After concentration and purification (SiO2, EtOAc/hexanes), 3-(4-chloro-phenyl)-1-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester was obtained. This intermediate was then diluted with CH2Cl2 (10 mL), and TFA (1 mL) was added. The mixture was stirred at RT for 4 h. The mixture was concentrated and the residue was purified (SiO2, 2 M NH3 in MeOH/CH2Cl2) to provide the title compound (40 mg). MS (ESI): exact mass calculated for C19H18ClN3, 323.12. found, m/z 324.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.46-7.40 (m, 4H), 7.36-7.32 (m, 5H), 3.09-3.07 (br m, 4H), 3.00-2.98 (br m, 2H), 3.92-2.90 (br m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=3)[NH2:24])[CH2:15][CH2:14]2)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[C:28](Cl)(=[O:30])[CH3:29]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([NH:24][C:28](=[O:30])[CH3:29])[CH:25]=[CH:26][CH:27]=3)[CH2:17][CH2:18]2)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)ccc(F)c2n1
Product: CC(=O)Nc1cccc(CCN2CCN(c3ccc(F)c4nc(C)ccc34)CC2)c1
Yield: 26 %

Procedure:
The title compound was prepared in 26% yield according to the general procedure for the preparation of amides (Method B) starting from 3-{2-[4-(8-fluoro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline and acetyl chloride.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4].Cl.[OH-].[Na+]>C1COCC1>[CH3:5][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([CH3:1])[CH2:3][NH2:4]
Reactant: CC(C)(C#N)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(CN)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
To a cooled solution of 2-methyl-2-(4-nitrophenyl)propanenitrile (670 mg, 3.5 mmol) in THF (15 mL) was added BH3 (1M in THF, 14 mL, 14 mmol) dropwise at 0° C. The mixture was warmed to room temperature and heated at 70° C. for 2 h. 1N HCl solution (2 mL) was added, followed by the addition of NaOH until pH>7. The mixture was extracted with ether and ether extract was concentrated to give 2-methyl-2-(4-nitrophenyl)propan-1-amine (610 mg, 90%), which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=9.0 Hz, 2H), 7.54 (d, J=9.0 Hz, 2H), 2.89 (s, 2H), 1.38 (s, 6H).
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[C:3]([C:5]1[NH:6][C:7]([Br:11])=[C:8]([Br:10])[CH:9]=1)=[O:4].Cl.N[C:16]1NC=C(CCCC(NCCCCCCCCCCCC)=O)N=1>>[Cl:13][C:2]([Cl:1])([Cl:12])[C:3]([C:5]1[N:6]([CH3:16])[C:7]([Br:11])=[C:8]([Br:10])[CH:9]=1)=[O:4]
Reactant: O=C(c1cc(Br)c(Br)[nH]1)C(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCNC(=O)CCCc1c[nH]c(N)n1
Agent: Cl
Product: Cn1c(C(=O)C(Cl)(Cl)Cl)cc(Br)c1Br
Yield: 96 %

Procedure:
Using the same general procedure as used for the synthesis of 2,2,2-trichloro-1-(4,5-dibromo-1H-pyrrol-2-yl)-ethanone 8, 5.00 g of 2-trichloroacetyl-1-methylpyrrole 12 gave 8.14 g (96%) of the title compound 14 as white needles. 1H NMR (300 MHz, DMSO-d6) δ 7.60 (s, 1H), 3.96 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 170.86, 123.81, 122.68, 120.58, 99.58, 94.89, 37.60; HRMS (FAB) calcd for C7H4Br2Cl3NO (M+) 380.7725, found 380.7744.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@H:3]1[NH2:13].[C:14](=S)=[S:15].O>C(O)C>[F:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C@H:2]1[NH:1][C:14](=[S:15])[NH:13][C@@H:3]1[CH2:4][CH2:5]2
Reactant: N[C@@H]1CCc2cc(F)ccc2[C@H]1N
Reactant: S=C=S
Solvent: O
Solvent: CCO
Product: Fc1ccc2c(c1)CC[C@H]1NC(=S)N[C@H]21
Yield: 82 %

Procedure:
Trans-1,2-diamino-6-fluoro-1,2,3,4-tetrahydronaphthalene (3.84 g, 21.3 m mol) was dissolved in ethanol (40 ml) and carbon disulfide (1.4 ml, 23.4 m mol) was added to the solution. After the resulting white suspension was stirred for a while, water (20 ml) was added to the suspension and they were heated under reflux for 30 minutes. The reaction mixture was cooled with ice and the precipitate was filtered. The solid was washed in turn with water (three portions of 20 ml, totaling 60 ml), ethyl ether (20 ml) and n-hexane (50 ml) and dried under vacuum to give trans-7-fluoro-3a,4,5,9b-tetrahydronaphth[1,2-d]imidazoline-2-thione as a yellowish grey solid (3.88 g, 17.4 m mol) in 82% yield. The product was recrystallized from acetone-acetonitrile to give light-yellow needles melting at 256.5° to 257.5° C. (decomposition). The data on spectroscopy were as follows:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[S:13][C:12]([CH:14]=[O:15])=[N:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[BH4-].[Na+]>CO>[F:16][C:2]([F:1])([F:17])[C:3]([C:9]1[S:13][C:12]([CH2:14][OH:15])=[N:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: O=Cc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29.8 %

Procedure:
To a stirring solution of 5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazole-2-carbaldehyde (1.791 mmol, 500 mg) in methanol (4 mL) was added sodium borohydride (5.37 mmol, 203 mg). The mixture was stirred at room temperature for 90 minutes before concentrating under reduced pressure. The resulting residue was dissolved in dichloromethane (2 mL)/methanol (0.5 mL) and filtered through a plug of silica, washing with 20% methanol/80% dichloromethane. The filtrate was concentrated under reduced pressure to afford the title compound (150 mg). MS (ESI) m/z 280.0 [M−H]
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:37]=[CH:36][C:26]2[N:27]([CH3:35])[C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=2[CH:24]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[Cl:21][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:22][C:23]2[CH:37]=[CH:36][C:26]3[N:27]([CH3:35])[C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: CN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4N(C)S(C)(=O)=O)n3)ccc21
Yield: 54.4 %

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-methyl-methanesulfonamide (79 mg, 0.22 mmol), 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (49 mg, 0.22 mmol), and 10-Camphorsulfonic acid (80 mg, 0.34 mmol) in Isopropyl alcohol (3 mL) and was heated in a microwave vial for 2 h at 120° C. Upon cooling, the mixture was treated with MP-Carbonate (2.69 mmol/g loading; 0.29 g, 0.78 mmol) for 1 h, was filtered and was concentrated in vacuo. Chromatography (ISCO, 2×12 g silica gel, 0-80% EtOAc:Hex) afforded N-{(1R,2R)-2-[5-Chloro-2-(1,5,5-trimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-N-methyl-methanesulfonamide as a white foam (64 mg, 53%). LCMS: 535 (M+H), 1H-NMR (CDCl3): 7.92 (s, 1H), 7.75 (d, 1H, J=8.5 Hz), 7.29 (s, 1H), 7.11 (d, 1H, J=8.5 Hz), 6.85 (s, 1H), 5.65 (d, 1H, J=7.8 Hz), 4.08 (m, 1H), 3.75 (m, 1H), 3.29 (s, 3H), 2.84 (s, 3H), 2.74 (s, 3H), 2.41 (m, 1H), 2.37 (m, 2H), 2.04 (m, 1H), 1.84 (m, 3H), 1.67 (m, 1H), 1.25-1.5 (m, 10H).
Reaction SMILES: [NH2:1][C@:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[O:5][CH2:4][C@@H:3]1[CH2:13][OH:14].[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C@:2]([NH:1][C:25]([NH:24][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[S:26])([CH3:15])[C@@H:3]([CH2:13][OH:14])[CH2:4][O:5]2)=[CH:10][CH:9]=1
Reactant: C[C@@]1(N)c2ccc(F)cc2OC[C@@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: C[C@@]1(NC(=S)NC(=O)c2ccccc2)c2ccc(F)cc2OC[C@@H]1CO
Yield: 93.9 %

Procedure:
A solution of ((3S,4S)-4-amino-7-fluoro-4-methylchroman-3-yl)methanol from step F3 (795 mg, 3.76 mmol), and benzoyl isothiocyanate (614 mg, 3.76 mmol) in THF (50 mL) was stirred at rt for 1.5 h. The resulting mixture was concentrated in vacuo. The crude residue was purified using silica gel column chromatography (95:5 chloroform/MeOH) to afford rel-N-(((3S,4S)-7-fluoro-3-(hydroxymethyl)-4-methylchroman-4-yl)carbamothioyl)benzamide (1.32 g, 3.53 mmol, 94% yield). LCMS (M+Na)+=397.2. 1H NMR (500 MHz, DMSO-d6) δ 11.45 (s, 1H), 11.26 (s, 1H), 7.91 (dd, J=8.4, 1.2 Hz, 2H), 7.68-7.58 (m, 1H), 7.57-7.41 (m, 3H), 6.86 (td, J=8.5, 2.7 Hz, 1H), 6.70 (dd, J=10.4, 2.7 Hz, 1H), 4.84 (t, J=4.7 Hz, 1H), 4.56 (dd, J=11.4, 3.1 Hz, 1H), 4.20 (dd, J=11.4, 1.6 Hz, 1H), 3.64-3.52 (m, 1H), 3.26-3.12 (m, 2H), 2.07 (s, 2H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([NH2:8])[CH2:5][CH2:6][CH3:7].[N:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21])=[C:10]=[O:11]>>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[NH:9][C:10]([NH:8][CH:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1])=[O:11]
Reactant: COc1ccc(N=C=O)c(OC)c1
Reactant: CCCC(N)CCC
Product: CCCC(CCC)NC(=O)Nc1ccc(OC)cc1OC
Yield: 88 %

Procedure:
Prepared in a similar manner to example 158 using heptan-4-amine and 1-isocyanato-2,4-dimethoxybenzene. Yield: 88%. mp: 172-173° C. 1H NMR (500 MHz, CDCl3): δ 0.93 (t, 6H), 1.45 (m, 8H), 3.82 (s, 3H), 3.83 (m, 1H), 3.84 (s, 1H), 4.32 (br s, 1H), 6.34 (br s, 1H), 6.49 (d, 1H), 6.50 (s, 1H), 7.71 (d, 1H). MS (M+H, 295).
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33]>C1COCC1>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[CH2:25][CH:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]1=[O:13]
Reactant: Fc1cccc(Cl)c1CBr
Reactant: O=C1CCCCN1C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2c(F)cccc2Cl)CCCN1C1CCCCC1
Temperature: -78 °C
Yield: 59 %

Procedure:
Dissolve 1-cyclohexyl-piperidin-2-one (0.2 g, 1.10 mmol) in dry THF (11 mL) cool to −78° C. and add lithium bis(trimethylsilyl)amide (1.66 mL of 1.0 M solution in THF, 1.66 mmol). After 15 min add 1-bromomethyl-2-chloro-6-fluorobenzene (0.49 g, 2.21 mmol), and allow the mixture to warm to room temperature over 15 h. Wash the mixture with brine, dry the organic layer over sodium sulfate and evaporate. Purify the residue by chromatography on silica gel (eluting 0% to 100% ethyl acetate in hexane) to give the desired product (0.21 g, 59%). MS (ES+) m/z=324 (M+H)+.