Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)/[C:9]1=[O:26])=O)(C)(C)C.C([Si](C)(C)[O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([O:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=2[CH:47]=[N:48][C:49]([O:51][Si](C)(C)C)=[CH2:50])[CH2:35][CH2:34]1)(C)(C)C>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:26])[C:10]3([CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[CH2:51][C:49](=[O:50])[NH:48][CH:47]3[C:41]3[CH:42]=[C:43]([Cl:46])[CH:44]=[CH:45][C:40]=3[O:39][C@H:36]3[CH2:35][CH2:34][C@@H:33]([OH:32])[CH2:38][CH2:37]3)[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(Cl)ccc1O[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Cl)ccc2O[C@H]2CC[C@@H](O)CC2)N1

Procedure:
In a manner similar to the method described in example 1e, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 1b (0.47 g, 1.2 mmol) was reacted 1-[2-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (3 mmol) in toluene to give racemic(2′R, 3R, 4′S)-6-chloro-2′-[5-chloro-2-(cis-4-hydroxy-cyclohexyloxy)-phenyl]-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a pale yellow solid (Yield 0.3 g, 42%)
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O-:10][CH2:11][CH3:12].[Na+]>C(O)C.O>[Br:1][C:2]1[C:3]([O:10][CH2:11][CH3:12])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(Cl)c(Br)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ncc(C)cc1Br
Temperature: 100 °C
Reaction time: 48 h
Yield: 71.7 %

Procedure:
To a solution of 3-bromo-2-chloro-5-methylpyridine (4.00 g, 19.37 mmol) in ethanol (100 mL) was added sodium ethoxide (6.59 g, 96.9 mmol) in three portions. The mixture was stirred under nitrogen at 100° C. for 2 days. The reaction was cooled to room temperature, diluted with water and extracted with DCM. The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 20%, EtOAc/hexanes) afforded the title compound (3.00 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ 7.94 (dd, J=0.8, 2.3 Hz, 1H), 7.89-7.82 (m, 1H), 4.31 (q, J=7.0 Hz, 2H), 2.18 (t, J=0.8 Hz, 3H), 1.30 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[N:8]([CH:9]=1)[CH:7]=[CH:6][S:5]2.S(=O)(=O)(O)O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:15](=[O:17])[CH3:16])[CH:7]=[CH:6][S:5]2
Reactant: CC(=O)OC(C)=O
Reactant: Clc1cn2ccsc2n1
Agent: O=S(=O)(O)O
Product: CC(=O)c1c(Cl)nc2sccn12
Temperature: 140 °C
Reaction time: 4 h

Procedure:
To a solution of 6-chloroimidazo[2,1-b]thiazole (7.93 g, 50 mmol) in acetic anhydride (150 mL) was added 0.2 ml of concentrated sulfuric acid. The mixture was stirred at 140° C. for 4 hours. The mixture was evaporated to dryness and the residue was taken up in water (300 mL), and the pH adjusted to pH ˜10 with aqueous NaOH. The resulting precipitate was filtered, washed with water and vacuum dried, providing the title compound. MS: (ESI(+)) m/e 200.8 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CO.[OH-].[K+].[CH2:15]([O:22][C:23](=[O:35])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH:32]=[O:33])[C:26]=1[F:34])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>>[CH2:15]([O:22][C:23](=[O:35])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH:32]([OH:33])[C:10]2[C:4]3[C:5](=[N:6][CH:7]=[CH:2][CH:3]=3)[NH:8][CH:9]=2)[C:26]=1[F:34])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Reactant: Clc1cnc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(F)c(C(O)c2c[nH]c3ncccc23)c1F)OCc1ccccc1
Reaction time: 8 h
Yield: 50.6 %

Procedure:
Into a round bottom flask was added 5-chloro-1H-pyrrolo[2,3-b]pyridine (80, 0.524 g, 3.43 mmol, prepared as described in Example 9) in methanol (5.00 mL, 0.123 mol). Potassium hydroxide (0.800 g, 14.2 mmol) and (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (614, 1.02 g, 3.5 mmol) were added and the reaction mixture was stirred overnight. The reaction mixture was poured into 1N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and crystallized from ethyl acetate to give compound 615 (710 mg, 46%). MS (ESI) [M+H+]+=444.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4](Br)[CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([S:31]([O-:33])=[O:32])[CH:28]=[CH:29][CH:30]=1.[Na+]>>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=2)(=[O:33])=[O:32])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Br)cc3c2C1
Reactant: O=S([O-])c1cccc(C(F)(F)F)c1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4cccc(C(F)(F)F)c4)cc3c2C1
Yield: 33 %

Procedure:
The product of Example 44, step B was coupled with sodium 3-trifluoromethylbenzenesulfinate using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 3:2 hexane/ethyl acetate) provided tert-butyl 6-chloro-8-(3-trifluoromethylphenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (130 mg, 33%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.94-8.06 (m, 1H), 7.86-7.81 (m, 2H), 7.73-7.63 (m, 1H), 4.58 (m, 2H), 3.84 (m, 2H), 2.92 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:19][C:18]3[CH:17]=[N:16][N:15]([CH3:20])[C:14]=3[NH:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]=O)[CH2:31][CH2:30]1)=[O:28].[CH2:37]([NH:41][CH3:42])[CH2:38][CH2:39][CH3:40].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CN(C=O)C>[CH2:37]([N:41]([CH2:35][CH:32]1[CH2:31][CH2:30][N:29]([C:27](=[O:28])[CH2:26][CH2:25][C:3]2[CH:4]=[CH:5][C:6]([C:8]([N:10]3[CH2:19][C:18]4[CH:17]=[N:16][N:15]([CH3:20])[C:14]=4[NH:13][C:12]4[CH:21]=[CH:22][CH:23]=[CH:24][C:11]3=4)=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:34][CH2:33]1)[CH3:42])[CH2:38][CH2:39][CH3:40]
Reactant: CCCCNC
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCN(C)CC1CCN(C(=O)CCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4ccccc43)cc2C)CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A solution of 1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidine-4-carbaldehyde from Example E58.1 (2.43 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of butyl-methyl-amine (0.43 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and the mixture was heated at 50° C. for 3 h then stirred at room temperature for 2 days. A solution of sodium tri-acetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added and the mixture was stirred for 20 h at room temperature. Solvents were removed in vacuo to yield the title compound. MS: (ESI)+:[M+H]+=557.6
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C.O>[F:12][C:11]([F:14])([F:13])[C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)=[O:15]
Reactant: O=C(Nc1ccc(CBr)c(C(F)(F)F)c1)C(F)(F)F
Reactant: C1CCNCC1
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc(CN2CCCCC2)c(C(F)(F)F)c1)C(F)(F)F

Procedure:
To a solution of N-(4-bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide (Stage 128.3; 1.465 g, 4.19 mmol) in acetonitril (35 ml) under N2-atmosphere, piperidine (1.25 ml, 12.7 mmol) is added. After 30 min at rt the reaction mixture is diluted with water and partially concentrated in vacuo. The aqueous residue Is acidified to pH 5 by addition of 0.1 N HCl and extracted 3× with AcOEt. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; hexane/AcOEt 3:2) gives the title compound: MS: [M+1]+=355; 1H-NMR (DMSO-d6): 11.48 (s, HN), 8.02 (s, 1H), 7.91 (dd, 1H), 7.77 (d, 1H), 3.52 (s, 2H), 2.32 (sb, 4H), 1.50 (m, 4H), 1.40 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[OH-].[Na+].[CH:13](O)=[O:14]>>[CH:13]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1)=[O:14]
Reactant: NC(=O)c1ccc(N)nc1
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1ccc(NC=O)nc1
Temperature: 100 °C

Procedure:
6-Aminonicotinamide, 5.6 g, was added to 90% formic acid, 15 ml. After all the crystals were dissolved, the clear solution was heated to 100° C. for 10 minutes. The mixture was cooled and then 4N NaOH was added to adjust the pH to 2.8. The white crystals which formed were separated by filtration and were washed once with cold water followed by acetone wash. The yield of 6-formylaminonicotinamide was 5.6 g. This product had Rf value of 0.53 on thin-layer chromatogram using a solvent system of benzene:methanol, 1:1.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:17]1)=[O:13].C(N(CC)CC)C.N>C(Cl)(Cl)Cl>[C:1]([NH:10][CH2:11][C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:17]1)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(=O)NCC1CCCN(Cc2ccc(Cl)cc2)C1
Reactant: O=C(Cl)c1ccccc1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1ccccc1)NCC1CCCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A chloroform (0.4 mL) solution of benzoyl chloride (0.060 mmol) was added to a chloroform (1.0 mL) solution of 3-[(glycylamino)methyl]-1-(4-chlorobenzyl)piperidine (0.050 mmol) and triethylamine (0.070 mmol). The resulting reaction mixture was shaken at room temperature for 2.5 hours, and an (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol) was then added to the obtained mixture. The resulting mixture was shaken at room temperature for 12 hours and filtered, and the resin was washed with dichloromethane (0.5 mL). The filtrate and washings were combined, and dichloromethane (4 mL) was added. The obtained mixture was washed with an 2 M aqueous solution of NaOH (0.5 mL) and concentrated to thereby afford 3-[(N-benzoylglycyl)amino]methyl-1-(4-chlorobenzyl)piperidine (Compd. No. 434) -(14.7 mg, 74%). The purity was determined by RPLC/MS (91%). ESI/MS m/e 400 (M++H, C22H26ClN3O2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=2[F:17])=[CH:4][N:3]=1.[C:18]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)(=[O:25])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[C:26]([S:23]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:24])=[O:25])=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:12][C:11]=2[F:17])=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Reactant: N#Cc1cc(N)ncc1-c1ccc(Br)cc1F
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cc2C#N)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 2-amino-5-(4-bromo-2-fluorophenyl)pyridine-4-carbonitrile and (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid. MS (ESI): mass calcd. for C22H21FN4O2S, 424.14; m/z found, 425.1 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.18 (d, J=7.8, 1H), 8.01 (s, 1H), 7.64-7.58 (m, 1H), 7.57-7.51 (m, 1H), 7.46-7.28 (m, 4H), 3.91 (s, 1H), 1.04 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]1[C:2]2[O:1][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4][C:3]=2[CH:6]=[CH:7][CH:8]=1
Reactant: COCCCOc1cccc(C=O)c1O
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cccc(OCCCOC)c2o1

Procedure:
A suspension of 1.95 g of 2-hydroxy-3-(3-methoxypropoxy)benzaldehyde, 1.16 ml of ethyl chloroacetate and 2.51 g of potassium carbonate in 100 ml of N,N-dimethylformamide is stirred at reflux over 19 hours. The reaction mixture is cooled, poured onto water (at 0° C.), stirred and subsequently extracted with dichloromethane (2×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.50 (1:1 EtOAc-heptane); Rt=4.72.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (1.3 g, 6.4 mmol) in MeOH (10 mL) was added sodium borohydride (0.29 g, 7.7 mmol), and the reaction was stirred at room temperature for 5 minutes. After aqueous work-up, the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[C:9]1[N:14]=[C:13]2[NH:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:17][C:12]2=[C:11]2[N:23]([CH3:26])[CH:24]=[N:25][C:10]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38](I)[CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[C:9]1[N:14]=[C:13]2[N:15]([CH2:38][CH3:39])[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:17][C:12]2=[C:11]2[N:23]([CH3:26])[CH:24]=[N:25][C:10]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cc2c(nc(N(Cc3ccc(OC)cc3OC)C(=O)OC(C)(C)C)c3ncn(C)c32)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c3c(ncn3C)c(N(Cc3ccc(OC)cc3OC)C(=O)OC(C)(C)C)nc2n1CC
Temperature: 60 °C

Procedure:
To a solution of ethyl 4-(tert-butoxycarbonyl(2,4-dimethoxybenzyl)amino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxylate (example 1F, 5.046 g, 9.90 mmol) in DMF (49.5 mL) was added ethyl iodide (1.601 mL, 19.81 mmol) and cesium carbonate (6.45 g, 19.81 mmol). The reaction mixture was heated at 60° C. 60 min and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and vacuum filtered to remove cesium carbonate. Saturated aqueous sodium bicarbonate was added and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with 10% lithium chloride (3×), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Crude product was carried forward.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)[N:13]=2)=[CH:10][N:9]=[C:8]1[CH3:26].N1C=CC=CC=1>C(Cl)Cl>[CH3:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:21][CH:20]=3)[N:13]=2)=[CH:10][N:9]=[C:8]1[CH3:26]
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(N)cc3)n2)n1C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ncc(-c2ccnc(Nc3ccc(NS(C)(=O)=O)cc3)n2)n1C
Temperature: 4 °C
Yield: 65.4 %

Procedure:
Methanesulphonyl chloride (0.055 ml, 0.711 mmole) was added to a solution of 4-(1,2-dimethylimidazol-5-yl)-2-(4-aminoanilino)pyrimidine (Example 165; 0.18 g, 0.64 mmole) and pyridine (0.052 ml, 0.64 mmole) in DCM (2.0 mL) cooled at 4° C. The mixture was allowed to warm to ambient temperature. The mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution and EtOAc. The organic layer was separated, the volatiles evaporated and the residue purified by column chromatography on silica gel eluting with DCM/7M methanolic ammonia (96:4) to give the title compound (0.15 g, 65%) as a solid. NMR: 2.36 (s, 3H), 2.90 (s, 3H), 3.91 (s, 3H), 7.06 (d, 1H), 7.14 (d, 2H), 7.57 (s, 1H), 7.64 (d, 2H), 8.33 (d, 1H), 9.37 (br s, 1H), 9.42 (s, 1H); m/z 359.
Reaction SMILES: [OH:1][CH2:2][CH2:3]CCCC1CCCC1=O.OCCCCCC1CCCC1=O.[C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39])(=[O:27])[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)C)(=O)C>>[C:2]([O:39][C:35]1[CH2:36][CH2:37][CH2:38][C:34]=1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:25](=[O:27])[CH3:26])(=[O:1])[CH3:3]
Reactant: CC(=O)OCCCCCC1CCCC1=O
Reactant: O=C1CCCC1CCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCCCCCC1=C(OC(C)=O)CCC1

Procedure:
A solution of 400 g. (2.04 moles, of a mixture of 2-(5-hydroxypentyl)cyclopentanone and 2-(5-acetoxypentyl)cyclopentanone (Example 55) and 4.0 g. of p-toluenesulfonic acid monohydrate in 1 l. of acetic anhydride is refluxed at a rate to maintain a steady distillation of acetic acid from the reaction through a helix-packed fractionation column. The reaction is continued with the addition of acetic anhydride to maintain a constant volume until complete conversion of starting materials to product is evident. The mixture is cooled and partitioned between 2 l. of hexane and 3 l. of cold water containing solid sodium bicarbonate to maintain a neutral pH. The organic phase is washed with saturated brine, dried (MgSO4), and evaporated to yield 452 g. of an oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][C:4]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([N:22]3[C:34](=[O:35])[C:33]4[S:32][C:31]5[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=5[C:25]=4[CH:24]=[N:23]3)[C:17]=2[CH:36]=[O:37])=[CH:3]1.[BH4-].[Na+]>CO>[OH:37][CH2:36][C:17]1[C:18]([N:22]2[C:34](=[O:35])[C:33]3[S:32][C:31]4[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=4[C:25]=3[CH:24]=[N:23]2)=[N:19][CH:20]=[CH:21][C:16]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1cc(-c2ccnc(-n3ncc4c5c(sc4c3=O)CCCC5)c2C=O)cc(Nc2ccccn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(-n3ncc4c5c(sc4c3=O)CCCC5)c2CO)cc(Nc2ccccn2)c1=O
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
To a solution of 178c (179 mg, 0.35 mmol) in methanol (6 mL) was added sodium borohydride (39 mg, 1.05 mmol) at 0° C. The reaction mixture was stirred for 30 minutes and quenched with water (1.0 mL). It was then concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 178 (100 mg, 56%). MS-ESI: [M+H]+ 513.3. 1H NMR (500 MHz, CDCl3) δ 8.81 (s, 1H), 8.68 (d, J=5.0 Hz, 1H), 8.32 (s, 1H), 8.27 (d, J=4.0 Hz, 1H), 7.94 (bs, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.58-7.56 (m, 2H), 6.85-6.80 (m, 2H), 4.47-4.45 (m, 2H), 4.38-4.36 (m, 1H), 3.74 (s, 3H), 3.01-2.99 (m, 2H), 2.89-2.87 (m, 2H), 2.02-1.99 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH:46]([NH:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([N:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:54][CH2:53]1)=[O:51])([CH3:48])[CH3:47]>>[CH:46]([NH:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([N:58]2[CH2:63][CH2:62][N:61]([C:21]([N:11]3[C@@:12]([C:14]4[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=4)([CH3:13])[C@@:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([CH3:38])[N:9]=[C:10]3[C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:31])[CH3:32])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[O:22])[CH2:60][CH2:59]2)[CH2:54][CH2:53]1)=[O:51])([CH3:48])[CH3:47]
Reactant: CC(C)NC(=O)N1CCC(N2CCNCC2)CC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCN(C(=O)NC(C)C)CC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-piperazin-1-yl-piperidine-1-carboxylic acid isopropylamide trifluoroacetate to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). LR-MS: 786.0 [(M+H)+]
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=2[O:10][CH2:11][CH:12]2[O:14][CH2:13]2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>C(O)(C)C>[CH3:1][C:2]1[N:3]([C:8]2[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=2[O:10][CH2:11][CH:12]([OH:14])[CH2:13][NH:22][CH:19]([CH3:21])[CH3:20])[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CC(C)N
Reactant: Cc1ccc(C)n1-c1ccccc1OCC1CO1
Solvent: CC(C)O
Product: Cc1ccc(C)n1-c1ccccc1OCC(O)CNC(C)C

Procedure:
30 g of 1-[o-(2,5-dimethyl-pyrrol-1-yl)-phenoxy]-2,3-epoxy-propane, dissolved in 200 ml of isopropanol, are mixed with 60 ml of isopropylamine and the mixture is heated to the boil under reflux for 2 hours. The oil which remains after evaporation is recrystallised from petroleum ether with addition of active charcoal and gives 1-[o-(2,5-dimethyl-pyrrol-1-yl)-phenoxy]-3-isopropylamino-2-propanol of melting point 73°-75° C. Its neutral fumarate melts at 186°-188° C (from acetone).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH3:19])[C:13]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=1)=[O:4].[OH-].[Na+].Cl>CO>[CH2:18]([N:14]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]2[C:15]1=[CH:16][CH:17]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[CH3:19]
Reactant: CCn1c2c(c3cc(C(=O)OC)ccc31)CCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1c2c(c3cc(C(=O)O)ccc31)CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
Then, 480 mg of the N-ethyl-1,2,3,4-tetrahydrocarbazole-6-carboxylic acid methyl ester was dissolved in 5 mL of methanol, added with 4 mL of 4 N aqueous sodium hydroxide, and stirred at room temperature for 2 hours. Subsequently, the reaction mixture was cooled and then neutralized with hydrochloric acid, and the deposited precipitates were collected to obtain 400 mg of N-ethyl-1,2,3,4-tetrahydrocarbazole-6-carboxylic acid. The obtained N-ethyl-1,2,3,4-tetrahydrocarbazole-6-carboxylic acid (73 mg), 6-(1-naphthalenesulfonyl)-aminopentylamine (100 mg) obtained in Example 36 and WSC (68 mg) were dissolved in 2 mL of DMF and the mixture was stirred at room temperature for 4 hours. The reaction mixture was added with water and extracted with ethyl acetate. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: chloroform/ethyl acetate=95/5) to obtain 50 mg of Compound 1-45.