Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C@@H:36](O)[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][C@@H:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Cl:29])[CH3:37])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Reactant: C[C@H](O)c1ccccc1Cl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@H](C)c1ccccc1Cl

Procedure:
In a similar manner as described for example B31, 2.1 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 1.18 g of (1S)-1-(2-chlorophenyl)ethanol, 3.33 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 2.3 g of di-tert-butyl azodicarboxylate in 60 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[F:23][CH:24]([F:46])[C:25]1[O:29][C:28]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:37][C:38]([C:42]([OH:44])=O)=[C:39]([CH3:41])[N:40]=3)[C:32]2=[O:45])=[CH:27][CH:26]=1.[NH2:47][CH2:48][C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1>>[F:23][CH:24]([F:46])[C:25]1[O:29][C:28]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:37][C:38]([C:42]([NH:47][CH2:48][C:49]4[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=4)=[O:44])=[C:39]([CH3:41])[N:40]=3)[C:32]2=[O:45])=[CH:27][CH:26]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)F)o3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(C(F)F)o3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 59 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-((5-(difluoromethyl)furan-2-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 59% yield: mp 142-143° C. (diethyl ether): 1H NMR (300 MHz, CDCl3) δ 8.60-8.53 (m, 1H), 8.51-8.44 (m, 1H), 7.72-7.62 (m, 1H), 7.28-7.19 (m, 1H), 6.59-6.57 (m, 1H), 6.54 (t, JH-F=54.2 Hz, 1H), 6.33-6.59 (m, 1H), 4.56 (d, J=5.8 Hz, 2H), 4.46 (s, 2H), 4.10-4.03 (m, 2H), 3.61-3.53 (m, 2H), 2.57 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6, 157.2, 155.1, 153.5, 151.4, 149.2, 148.8, 135.6, 133.9, 123.6, 117.1, 111.3, 109.7, 108.1, 105.0, 42.3, 42.0, 41.3, 40.4, 17.2; MS (ES+) m/z 448.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([NH:31][C:32]([NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C=NCc1ccccc1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)NCc4ccccc4)nc3cc21

Procedure:
Benzyl-3-[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-urea was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.48 mmol) and benzylisocyanate (0.05 ml, 0.41 mmol). After purification by flash chromatography (dichloromethane/methanol 94:6) the title compound was obtained as a light grey powder (26 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]([CH3:12])=[N:10][C:9]2[N:5]([N:6]=[C:7]3[C:15]([CH3:17])([CH3:16])[N:14]([C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:19])[CH2:13][C:8]3=2)[C:4]=1[CH3:33].C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O.[OH-].[Na+]>ClCCCl>[Cl:2][C:3]1[C:11]([CH3:12])=[N:10][C:9]2[N:5]([N:6]=[C:7]3[C:15]([CH3:16])([CH3:17])[N:14]([C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH:27]4[CH2:28][CH2:29][N:30]([CH3:36])[CH2:31][CH2:32]4)=[O:19])[CH2:13][C:8]3=2)[C:4]=1[CH3:33]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)C(C)(C)N(C(=O)c1ccccc1OC1CCNCC1)C3
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1nc2c3c(nn2c(C)c1Cl)C(C)(C)N(C(=O)c1ccccc1OC1CCN(C)CC1)C3
Yield: 79.6 %

Procedure:
A mixture of Example 100 (100 mg; 0.22 mmol; 1 eq.), paraformaldehyde (60 mg; 0.66 mmol; 3 eq.), sodium triacetoxyborohydride (93 mg; 0.44 mmol; 2 eq.) and AcOH (13 μL; 0.22 mmol; 1 eq.) in DCE (5 mL) was stirred at 65° C. for 16 hours. 1M NaOH was added and the two phases separated. The aqueous layer was extracted with DCM (2×). The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (5% to 20% MeOH in DCM) afforded the title compound (82 mg, 80%) as a colourless oil. 1H NMR (DMSO-d6) δ 7.44-7.32 (m, 1H), 7.24 (dd, J=7.4, 1.7 Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 7.06-6.96 (m, 1H), 4.58-4.42 (m, 2H), 4.42-4.25 (m, 1H), 2.83 (s, 3H), 2.54 (s, 3H), 2.48-2.34 (m, 2H), 2.15 (br s, 2H), 2.04 (s, 3H), 1.94-1.75 (m, 8H), 1.56 (br s, 2H). HPLC (max plot) 98.6%, Rt 3.15 min. UPLC/MS: (MS+) 468.5 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([NH:15][C:16]([NH:18][CH2:19]C(F)(F)F)=[O:17])[CH:12]=[CH:13][CH:14]=2)[O:3]1.FC(F)(F)CN>C1COCC1>[CH3:19][NH:18][C:16]([NH:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([B:4]2[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:24])([CH3:1])[O:3]2)[CH:10]=1)=[O:17]
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Agent: NCC(F)(F)F
Solvent: C1CCOC1
Product: CNC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1

Procedure:
Prepared as described for 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (I6), substituting methylamine in THF (2M) for 2,2,2-trifluoroethyl amine in Step 1. 1H NMR (400 MHz, CDCl3): 7.59-7.53 (2H, m), 7.50 (1H, d), 7.34 (1H, t), 2.83 (3H, s), 1.33 (12H, s).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].[C:16](Cl)(=[O:18])[CH3:17]>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=1[CH2:4][N:5]([CH2:6][CH3:7])[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(C)=O

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine and acetyl chloride.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]4)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C(O)C.C([BH3-])#N.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[CH2:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([CH2:22][NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:16]=[CH:15]4)[CH2:7][CH2:6]2)[CH2:1][CH2:2][CH2:3]1
Reactant: O=Cc1ccc2cc(OC3CCC4(CCCC4)CC3)ccc2c1
Reactant: NCCC(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCNCc1ccc2cc(OC3CCC4(CCCC4)CC3)ccc2c1
Temperature: 25 °C
Yield: 31 %

Procedure:
A solution of 6-(Spiro[4.5]dec-8-yloxy)-naphthalene-2-carbaldehyde (229.5 mg, 0.7441 mmol) and Beta-alanine (66.3 mg, 0.744 mmol) in ethanol (1 mL, 20 mmol) was heated to reflux for 2 h. The yellow solution was cooled to rt and sodium cyanoborohydride (56.1 mg, 0.893 mmol) was added and was heated to reflux for 1 h. After cooled down to rt, citric acid was added and concentrated down. Extraction with DCM and prep HPLC gave product as a white solid (88 mg, 31%). LCMS Rt=1.52 min m/z=382.30 [M+1]. 1H NMR (400 MHz, MeOD) δ=7.89 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.80 (d, =9.0 Hz, 1H), 7.48 (dd, J=1.7, 8.5 Hz, 1H), 7.27 (s, 1H), 7.19 (dd, J=2.3, 8.9 Hz, 1H), 4.55-4.44 (m, 1H), 4.35 (s, 2H), 3.36-3.32 (m, 2H), 2.76 (t, J=6.8 Hz, 2H), 2.09-1.33 (m, 16H).
Reaction SMILES: CS(O[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH2:23][O:24][CH3:25])=[CH:17][CH:16]=2)=[CH:11][N:10]=1)[CH2:7][CH3:8])(=O)=O.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1.C(N(CC)CC)C>C1COCC1>[N:26]1([CH:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH2:23][O:24][CH3:25])=[CH:17][CH:16]=3)=[CH:11][N:10]=2)[CH2:7][CH3:8])[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: c1c[nH]cn1
Reactant: CCC(OS(C)(=O)=O)c1ccc(-c2ccc(COCOC)cc2)cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(c1ccc(-c2ccc(COCOC)cc2)cn1)n1ccnc1
Temperature: 65 °C
Yield: 43.9 %

Procedure:
A mixture of 1-(5-(4-((methoxymethoxy)methyl)phenyl)pyridin-2-yl)propyl methanesulfonate (0.1 g, 0.27 mmol), 1H-imidazole (0.037 g, 0.54 mmol) and triethylamine (0.07 mL, 0.54 mmol) in THF (15 mL) was stirred and refluxed at 65° C. for 12 h, cooled to room temperature, poured into ice water (50 mL) and extracted with EtOAc (2×50 mL). The organic layer was separated, dried (Na2SO4), and the solvent was evaporated under vacuo. The resulting residue was purified by preparative TLC using 5% methanol in dichloromethane and isolated as light green viscous liquid (0.04 g, 44% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.86 (s, 1H), 8.06 (dd, 1H), 7.81 (s, 1H), 7.69 (d, 2H), 7.44 (d, 2H), 7.37 (d, 1H), 7.30 (s, 1H), 5.36 (q, 1H), 4.65 (s, 2H), 4.56 (s, 2H), 3.30 (s, 3H), 2.25 (m, 2H), 0.81 (t, 3H). LC-MS: m/z 338.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>ClCCl>[CH2:29]([O:28][C:26]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-(aminomethyl)piperidine-1-carboxylate (0.611 g, 2.851 mmol) and diisopropylethylamine (0.479 g, 3.706 mmol) were dissolved in 30 mls of dry dichloromethane. To this mixture was added benzyl chloroformate (0.552 g, 3.136 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was then diluted with 50 mls of dichloromethane, washed once with 1N aqueous HCl, one with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under reduced pressure to 950 mgs (96%) of the title compound and used directly without further purification.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][C:10]([F:13])([F:12])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=4)=[N:19][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.[CH2:30]([N:32](CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.Cl.CN>C(OCC)(=O)C.CN(C)C=O>[CH:1]1([N:5]2[CH2:11][C:10]([F:12])([F:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]([NH:32][CH3:30])=[O:26])=[CH:28][CH:29]=4)=[N:19][C:6]2=3)[CH2:2][CH2:3][CH2:4]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: CCN(CC)CC
Agent: CN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCC2)CC(F)(F)C(=O)N3C)cc1
Reaction time: 0.25 h
Yield: 61.1 %

Procedure:
A mixture of 0.089 g (0.22 mmole) of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-11), 0.089 g (0.88 mmole) of triethylamine, 0.125 g (0.33 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes, then 0.022 g (0.33 mmole) of methylamine hydrochloride was added. The mixture was stirred for 3 hours, then taken up in 100 mL of ethyl acetate and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (gradient 100:0:0-92:8:0.3) to give 0.056 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-methyl-benzamide (I-13).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:13]1[CH:23]=[CH:22][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=2[CH:14]=1)=[O:12].C(N(CC)CC)C.O>O1CCCC1>[Cl:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:13]1[CH:23]=[CH:22][C:16]2[CH2:17][CH2:18][N:19]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:20][CH2:21][C:15]=2[CH:14]=1)=[O:12]
Reactant: O=C(CCCCCl)c1ccc2c(c1)CCNCC2
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)N1CCc2ccc(C(=O)CCCCCl)cc2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylsulfonyl chloride (804 μl) was added to a solution of 5-chloro-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanone (2.4 g) obtained in Reference Example 121 and triethylamine (1.67 ml) in tetrahydrofuran (30 ml). After stirring at room temperature for 60 minutes, water (50 g) was added, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give a pale yellow solid (2.2 g). Further recrystallization from ethanol-diethyl ether afforded the title compound as colorless crystals (1.92 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([NH:7][C:8]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]1)=[O:6].[CH3:15]I>CN(C)C=O>[CH3:3][O:4][C:5]([N:7]([CH3:15])[C:8]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]1)=[O:6]
Reactant: COC(=O)NC1(C(=O)OC)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)N(C)C1(C(=O)OC)CC1
Reaction time: 0.25 h

Procedure:
24.7 g of sodium hydride are added, in fractions, to a solution, cooled to 5° C., of 99.7 g of the compound obtained in Step 2 in 1.7 liters of anhydrous dimethylformamide. After 15 minutes at 5° C. and then 3 hours at ambient temperature, 38.2 ml of methyl iodide are added dropwise. After reacting for 20 hours, the mixture is evaporated. The residue is taken up in ether and then treated in conventional manner. Chromatography over silica gel (dichloromethane) allows the expected product to be isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH2:36][O:37][CH3:38])=[C:6]([C@@:8]([C:21]2[CH:26]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:24]=[C:23]([F:33])[C:22]=2[Cl:34])([NH:14][S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[C:9](OCC)=[O:10])[CH:7]=1.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH2:36][O:37][CH3:38])=[C:6]([C@:8]([NH:14][S@:15]([C:17]([CH3:18])([CH3:19])[CH3:20])=[O:16])([C:21]2[CH:26]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:24]=[C:23]([F:33])[C:22]=2[Cl:34])[CH2:9][OH:10])[CH:7]=1
Reactant: CCOC(=O)[C@](N[S@@](=O)C(C)(C)C)(c1cc(Br)ccc1OCOC)c1cc(N2CCOCC2)nc(F)c1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOc1ccc(Br)cc1[C@](CO)(N[S@@](=O)C(C)(C)C)c1cc(N2CCOCC2)nc(F)c1Cl
Reaction time: 1 h
Yield: 57.1 %

Procedure:
A solution of (S)-ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-2-((S)-1,1-dimethylethylsulfinamido)acetate (3.56 g, 5.59 mmol) in THF (60 mL) was cooled to 0° C. and treated drop wise with DIBAL (1M in THF) (22.36 mL, 22.36 mmol) under nitrogen atmosphere. After 1 h additional 10 mL DIBAL solution were added at RT. After 12 h at RT additional 10 mL DIBAL solution were added. After 30 min aqueous saturated solution of potassium sodium tartrate was added, followed by EtOAc. The reaction mixture was allowed to stir vigorously for 1 h. The organic phase was separated, washed with aqueous saturated solution of potassium sodium tartrate and dried over MgSO4. The solvent was removed under reduced pressure and the crude material was purified by silica gel chromatography (20-100% EtOAc/hexane) to provide 1.90 g of (S)—N—((S)-1-(5-bromo-2-(methoxymethoxy)phenyl)-1-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-2-hydroxyethyl)-2-methylpropane-2-sulfinamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N1C=CN=C1)([N:17]1C=CN=C1)=O.O.N>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([NH2:17])=[O:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cc(Br)cc2ccccc12
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cc(Br)cc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of 3-bromonaphthalene-1-carboxylic acid (0.30 g) in tetrahydrofuran (3 mL) was added 1,1′-carbonyldiimidazole (0.29 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To this reaction mixture was added ammonia water (1.0 mL, 28% aqueous solution), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was stirred at room temperature for 15 minutes. The precipitated solid was collected by filtration. The obtained solid was washed with water and 1 mol/L hydrochloric acid, and dried to give 3-bromonaphthalene-1-carboxylic amide (0.28 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH:17]=[CH:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][C@H:20]([C:31]1[NH:35][C:34]2[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:33]=2[N:32]=1)[CH2:21][CH2:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH:16]=[CH:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][C@H:20]([C:31]1[NH:35][C:34]2[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:33]=2[N:32]=1)[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: CC(C)(C)OC(=O)CCC[C@H](Nc1ncnc2cc(C(=O)N3CC=CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCC[C@H](Nc1ncnc2cc(C(=O)N3CC=CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 8c from 6-chloro-4-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-4-(tert.-butyloxycarbonyl)-butylamino]-7-(2,5-dihydropyrrol-1-yl-carbonyl)-quinazoline and trifluoroacetic acid in dichloromethane.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12]SC)=[CH:7][CH:6]=1)[CH3:3].[N+:16]([CH:19]=[C:20]([NH2:27])[NH:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)([O-:18])=[O:17]>>[CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12][NH:27][C:20]([NH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:19][N+:16]([O-:18])=[O:17])=[CH:7][CH:6]=1)[CH3:3]
Reactant: NC(=C[N+](=O)[O-])NC1CCCC1
Reactant: CSCCSCc1ccc(CN(C)C)o1
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NC2CCCC2)o1

Procedure:
24.54 grams of 2-[[5-[(dimethylamino)methyl]furfuryl]thio]ethylmethylsulphide are reacted with 42 grams of 2-nitro-N-cyclopentyl-1,1-ethenediamine at 80° C. for 3 hours. The mixture is cooled and the procedure described in Example 1 is followed. The product melts at 97°-103° C. Spectrophotometric analyses confirm its structure.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH2:10][C@@H:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[N:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH:10]=[C:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[N:2]1
Reactant: CCCN(CCC)[C@@H]1Cc2c(-c3ccon3)ccc3c2[C@H](CN3)C1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(-c4ccon4)c(c23)C1
Reaction time: 4 h
Yield: 14.2 %

Procedure:
A mixture of (-)(2aR,4S)-6-(3-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (400 mg, 1.2 mmol) and 1 g of MnO2 in 100 ml of CH2Cl2 was sonicated at 50-55 KHz for four hours. The reaction mixture was warmed to reflux during the time period. After four hours, the reaction mixture was filtered through a celite pad and the filtrate was concentrated to dryness in vacuo. The resulting residue was chromatographed (flash column, silica gel, EtOAc) to provide 55 mg of title product as an oil. MS m/e 323 (FD)
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:16])[C:5]1[C:10]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[I:15])[CH3:2].[CH:17]1(N)CC1>>[CH:1]1([NH:3][C:4](=[O:16])[C:5]2[C:10]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=2[I:15])[CH2:17][CH2:2]1
Reactant: CCNC(=O)c1c(I)cccc1[Si](C)(C)C
Reactant: NC1CC1
Product: C[Si](C)(C)c1cccc(I)c1C(=O)NC1CC1
Yield: 87 %

Procedure:
The acid chloride prepared in Example 207 was reacted with cyclopropylamine (3 eq) using General Method E1 to afford the title compound. Purification by recrystallization from hexanes gave 0.49 g of the title compound as white needles in 87% yield. m.p. 162-164° C.