Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:23]([O:31][CH2:32][C@@H:33]1[C@@H:37]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@:36]([F:48])([CH3:47])[C@H:35](O)[O:34]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Br)(Br)(Br)[Br:51]>CCOC(C)=O>[C:23]([O:31][CH2:32][C@@H:33]1[C@@H:37]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@:36]([F:48])([CH3:47])[C@@H:35]([Br:51])[O:34]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrC(Br)(Br)Br
Reactant: C[C@]1(F)[C@H](O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@@H]1Br
Temperature: -17 °C

Procedure:
Anhydrous dichloromethane (5.6 L) was charged into a reactor and cooled to −22° C. or below. Triphenylphosphine (205.4 g, 0.783 mol) was added to the cold solvent and the suspension was stirred to form a solution. The lactol (2a, 209.4 g, 0.559 mol) in solid form was added to the cold solution and stirred for 15 mins. Carbon tetrabromide (278.2 g, 0.839 mol) was added portion-wise while maintaining the temperature of the solution between −22° C. to −20° C. under a flow of nitrogen gas (approx. 30 min). After finishing the addition of CBr4, the temperature was slowly raised to −17° C. over 20 mins. The reaction was judged to be >95% complete by TLC (Rfs 0.61 (α), 0.72 (β), 0.36 lactol; 20% EtOAc in hexanes). The reaction solution was immediately transferred to a vessel containing 230 g of flash chromatography grade silica gel (40-63 microns). The stirred mixture was immediately passed through a pad of silica gel (680 g) in a 2.5 L sintered glass Buchner funnel. The filtrate was concentrated under reduced pressure to about 800 mL and the ratio of α/β isomers of the crude product was 10:1 as determined by 1H-NMR. (CDCl3) δ=6.35, (s, αC1-H), 6.43, (d, βC1-H). The residue was purified by plug column chromatography using 2.1 kg of silica gel in a 6 L sintered glass Buchner funnel and eluted (via suction) with a stepwise gradient elution of 1%, 5%, 8% 12% EtOAc in hexane (ca 4 L each) to remove non-polar impurities followed by 12%, 25% EtOAc in hexane (6 L total) to elute the product. The product containing fractions were combined into two fractions, concentrated under reduced pressure, dried under vacuum (0.1 mmHg, ambient temp., 20 h) to colorless oils. Main fraction (197 g, 89% α/β=20:1). The alpha isomer crystallized from a small portion of the oil upon standing at 0° C. for several weeks to give large, thin plates, mp 59-61° C. The pure beta isomer crystallized from a mixture of alpha and beta product oil from an earlier less selective run to give needles, mp 77-79° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:10]([CH3:16])[C:11](=[O:13])[CH3:12])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CI
Reactant: COc1ncc(Br)cc1NC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(Br)cc1N(C)C(C)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To N-(5-bromo-2-methoxy-pyridin-3-yl)-acetamide (Stage 62.1.3, 100 mg, 0.408 mmol) DMF (1 ml) was added NaH 55% in oil (19.6 mg, 0.45 mmol). The reaction mixture was stirred for 10 min at rt then was added MeI (0.031 ml, 0.49 mmol). The reaction mixture was stirred for 1 h at rt then quenched with brine and extracted with EtOAc (2×). The organic layers are washed with brine (3×), dried over Na2SO4, filtered and evaporated. The crude product was purified by Prep.HPLC. The fractions containing the product were collected together and basified with NaHCO3, before being concentrated and extracted with EtOAc (3×). The organic layers were dried over Na2SO4, filtered and evaporated to dryness to give the title compound as an off-white solid (HPLC: tR 2.75 min (Method A); M+H=259, 261 MS-ES).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][CH:11]([OH:24])[CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH2:1]([O:8][C:9](=[O:25])[CH2:10][CH:11]([O:24][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CC(O)CNC(=O)OCc1ccccc1)OCc1ccccc1
Product: CS(=O)(=O)OC(CNC(=O)OCc1ccccc1)CC(=O)OCc1ccccc1

Procedure:
4-Benzyloxycarbonylamino-3-methanesulfonyloxy-butyric acid benzyl ester was prepared by an analogous procedure as described in example 26i) starting from 6.7 g (19.6 mmol) 4-benzyloxycarbonylamino-3-hydroxy-butyric acid benzyl ester and 1.84 ml (1.2 equiv.) methanesulfonyl chloride. 4-Benzyloxycarbonylamino-3-methanesulfonyloxy-butyric acid benzyl ester was obtained in crude form as yellow oil. Yield: 8.5 g.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24]Cl>>[Cl:19][C:18]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:24][C:23]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:21]([Cl:20])[CH:22]=3)[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=3)=[N:6][C:5]=2[CH:17]=1
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Product: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3n2Cc2ccc(Cl)c(Cl)c2)cc1

Procedure:
5,6-Dichloro-1-(3,4-dichlorobenzyl)-2-(4-formylphenyl)benzimidazole was prepared from 5,6-dichloro-2-(4-formylphenyl)benzimidazole obtained in Example 13 and 3,4-diclorobenzyl chloride by following General Procedure 3.
Reaction SMILES: FC(F)(F)C(O)=O.[I:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][NH:13][CH2:12]2.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>N1C=CC=CC=1>[I:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH2:12]2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Ic1ccc2c(c1)CNC2
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A mixture of the product of Step A (0.77 g; 2.15 mmol) and (BOC)2O (0.7 g; 3.2 mmol) in anhydrous pyridine (3 ml) was stirred for 1 h at ˜70° C. After removing solvents under reduced pressure, the residue was diluted to 20 ml with Et2O. The insoluble material was filtered off, and filtrate was washed with diluted HCl (5 ml), saturated NaHCO3 (5 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2; CH2Cl2:hexane 1:1) to give title compound (0.58 g; 78%) as creamy oil. 1H-NMR (CDCl3) 1.49 (5, 9H); 4.58-4.63 (m, 4H); 6.9-7.04 (m, 1H); 7.5-7.63 (m, 2H).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21](O)([CH2:24][CH3:25])([CH3:23])[CH3:22]>O>[C:1]([O:20][C:21]([CH2:24][CH3:25])([CH3:23])[CH3:22])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CCC(C)(C)O
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC(C)(C)CC
Temperature: 60 °C

Procedure:
Oleic acid (purity greater than 99%; 828 mg) was mixed with t-amyl alcohol (purity greater than 99%; 258 mg) together with 23 mg of distilled water. To this was added 62.5 mg of immobilised Candida antarctica liplase A (code SP433, ex Novo Industri, Denmark) as in Example I. The temperature of the reaction mixture was raised to 60° C. After 22 hours the amount of t-amyl oleate formed in the reaction was determined by GC analysis of the sample. 70.4 mg was removed and the mixture eluted down an alumina column (basic activity 2) to remove free fatty acid, using 60-80 petroleum ether as the eluant. 2.5 mg of eicosane was used as an internal standard for GC analysis. A final product yield of 14.8% based on oleic acid was achieved. Confirmation of the product identity was by GCMS.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[N:6]([CH3:31])[C:7]3[C:12]([N:13]=2)=[C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:10]=[C:9]([N:20]2[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=[C:21]2[CH2:29][CH3:30])[N:8]=3)[CH2:2]1.[O:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:29]([C:21]1[N:20]([C:9]2[N:8]=[C:7]3[C:12]([N:13]=[C:5]([CH:3]4[CH2:2][N:1]([CH:35]5[CH2:36][CH2:37][O:32][CH2:33][CH2:34]5)[CH2:4]4)[N:6]3[CH3:31])=[C:11]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:10]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)[CH3:30]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CNC3)n(C)c2n1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CN(C4CCOCC4)C3)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 4-(8-(azetidin-3-yl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine 680 (100 mg, 0.24 mmol), tetrahydropyran-4-one (34 mg, 0.33 mmol) and 4 Å powdered molecular sieves (130 mg) in DCE (3 mL) was stirred for 5.5 h before the addition of sodium triacetoxyborohydride (101 mg, 0.48 mmol). The resulting mixture was allowed to stir for 16 h at r.t, then filtered through Celite®, washing with DCM. The filtrate was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-30%) followed by Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH. The resulting solid was triturated with EtOAc affording 747 as a white powder (37 mg, 31%). LCMS (method I): RT 2.46 min, [M+H]+ 503.1. 1H NMR (CDCl3, 400 MHz): δ 8.01-7.97 (1 H, m), 7.75-7.74 (1 H, m), 7.26 (2 H, s), 4.37 (4 H, s), 4.02-3.80 (9 H, m), 3.70 (3 H, s), 3.51-3.37 (4 H, m), 3.34 (2 H, q, J=7.48 Hz), 2.41-2.33 (1 H, m), 1.77-1.66 (3 H, m), 1.43 (4 H, t, J=7.47 Hz)
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:17][C:16]=2[CH2:28][NH:29][CH3:30])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1([CH:37]=[CH:38][CH2:39][C:40](Cl)=[O:41])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([N:8]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[CH:17][C:16]=2[CH2:28][NH:29][CH3:30])[CH2:11][CH2:10]1)[C:40](=[O:41])[CH2:39][CH:38]=[CH:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CC=Cc1ccccc1
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NCc2ccccc2)CC1
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](N(Cc2ccccc2)C(=O)CC=Cc2ccccc2)CC1

Procedure:
from trans-N-benzyl-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)cyclohexylamine and 4-phenyl-3-butenoylchloride. Colourless oil. Rf value: 0.26 (alumina, petroleum ether/ethyl acetate/methanol=10:10:1, v:v:v).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.C([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[CH3:22])(=O)C>O>[CH3:22][CH:14]1[CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[C:18]([N+:1]([O-:4])=[O:2])[CH:17]=2)[NH:13]1
Reactant: CC(=O)N1c2ccccc2CC1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1Cc2cc([N+](=O)[O-])ccc2N1
Temperature: 7.5 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a cooled (0-10 C.) mixture of concentrated nitric acid (12 mL) and concentrated sulfuric acid (40 mL) was added 1-acetyl-2-methyl-indoline XII (12.5 g, 0.0713 moles), prepared by an analgous method to that described in Chem.Ber.; 14; 1881; 890, in small portions so that the internal temperature of the reaction remained between 10-20° C. The resulting mixture was allowed to stir at 5-10° C. overnight. The mixture was poured slowly into 300 mL of cold water and the precipitate that formed was collected by filtration, washed with water and redissolved in an ethanol-6N HCl solution and warmed to reflux for 30 minutes. The resulting solution was concentrated, EtOAc was added and the Ph of the solution adjusted to 10. The organic phase was separated and dried over MgSO4. The mixture was filtered, and evaporated and the crude material purified by column chromatography (50% EtOAc-Hexane) to give 3.31 g, 26% of 2-methyl-5-nitro-2,3-dihydro-1H-indole XIII: LRMS for C9H10N2O2 (M+H)+at m/z=179.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([NH:13][C:14](=[O:26])[N:15]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[C:11]([C:27]([O:29]CC)=O)[N:10]=2)[CH2:4][CH2:3]1.[NH2:32]C1C(C(OCC)=O)=NC(N[C@H]2CC[C@@H](O)CC2)=NC=1NC1C=CC=CC=1OC>ClCCl>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([NH:13][C:14](=[O:26])[N:15]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[C:11]([C:27]([NH2:32])=[O:29])[N:10]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@@H](O)CC2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@@H](O)CC2)nc(Nc2ccccc2OC)c1N
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CC[C@@H](O)CC3)nc21

Procedure:
Ethyl 2-(cis-4-hydroxycyclohexylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. Ethyl 5-amino-2-(cis-4-hydroxycyclohexylamino)-6-(2-methoxyphenyl-amino)pyrimidine-4-carboxylate (0.272 g, 0.678 mmol) and 1,1′-1,1′-carbonyldiimidazole (1.09 g, 6.78 mmol) in dichloromethane (20 mL) were reacted according to General Procedure F. A mixture of the title compound and the imidazole ester were formed and were taken on without further purification. MS (ESI) m/z 399 [M+1]+ (title compound), 522 [M+1]+ (imidazole urea).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[CH:25]=2)=[CH:3][CH:4]=1)([CH3:17])[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc(C(C)(C)C(=O)NCC(C)C)cc2)c1
Yield: 60 %

Procedure:
Prepared in a similar manner to example 8 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and 3-methoxyphenylboronic acid. Yield: 60%. 1H NMR (400 MHz, CDCl3): δ 0.8 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (t, 2H), 3.85 (s, 3H), 6.9 (dd, 1H), 7.1(s, 1H), 7.2(d, 1H), 7.4 (t, 1H), 7.45 (d, 2H), 7.6 (d, 2H). MS (M+H, 326).
Reaction SMILES: [CH:1]1([C:4]2[C:13](/[CH:14]=[CH:15]/[C:16](O)=[O:17])=[C:12]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.Cl.[CH3:41][NH:42][O:43][CH3:44]>ClCCl>[CH:1]1([C:4]2[C:13](/[CH:14]=[CH:15]/[C:16]([N:42]([O:43][CH3:44])[CH3:41])=[O:17])=[C:12]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: CNOC
Reactant: O=C(O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2.83 h

Procedure:
To a solution of (E)-3-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-acrylic acid (2.0 g, 6.0 mmol) in dichloromethane (25 ml) at −5° C. is added triethylamine (0.668 g, 6.6 mmol).and pivaloyl chloride (0.725 g, 6.0 mmol). After stirring at 0° C. for 170 min, N,O-dimethyl-hydroxylamine hydrochloride (0.59 g, 6.0 mmol) and triethylamine (1.22 g, 12.0 mmol) are added. After stirring in an ice bath for 90 min, and at room temperature for 30 min, more N,O-dimethylhydroxylamine hydrochloride (0.177 g, 1.8 mmol) is added and the reaction is stirred at room temperature for 17 h. After quenching with 0.2M citrate buffer pH5 (25 ml), the organic phase is separated and washed with 0.2M citrate buffer pH5 (25 ml), 0.2M phosphate buffer pH7 (25 ml) and water (25 ml). The water phases are extracted with dichloromethane (2×20 ml). Combined organic phases are dried over magnesium sulphate, evaporated, and the crude product chromatographed on silica gel (hexane/ethyl acetate 2:1) to afford (E)-3-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-N-methoxy-N-methyl-acrylamide (7). MS (ES): [M+H]+ 377, Mp. 155-156° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH3:8])=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]=1.[S:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1>>[CH2:7]([C:5]1[S:6][C:2]([C:17]2([OH:20])[CH2:18][CH2:19][S:14][CH2:15][CH2:16]2)=[CH:3][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:8]
Reactant: O=C1CCSCC1
Reactant: CCOC(=O)c1cc(Br)sc1CC
Product: CCOC(=O)c1cc(C2(O)CCSCC2)sc1CC
Yield: 72.9 %

Procedure:
An operation similar to that in Example 73 (1) was performed using ethyl 5-bromo-2-ethylthiophene-3-carboxylate (5.00 g) synthesized in Example 69 (4) and tetrahydro-4H-thiopyran-4-one (6.62 g) to give the title compound (4.16 g, 73%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:16]([OH:17])[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:17][C@@H:16]1[CH2:15][NH:14][CH2:13][C@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](NC(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CNC[C@H]1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of (3R,4R)-tert-butyl 3-(benzyloxycarbonylamino)-4-hydroxypyrrolidine-1-carboxylate (4.91 g, 14.60 mmol) in DCM (20 mL) was added TFA (11.25 mL, 146.0 mmol) and the mixture was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure. 6 N HCl in water (10 mL) was added. The mixture was stirred at ambient temperature for 30 minutes and neutralized with saturated sodium bicarbonate to about pH 8. It was extracted with DCM:IPA=4:1 (50 mL). The organic layer was separated, dried (sodium sulfate), filtered and concentrated under reduced pressure to give benzyl (3R,4R)-4-hydroxypyrrolidin-3-ylcarbamate (2.45 g, 71.0%) as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19](=[O:29])[C:20]1[CH:25]=[C:24]([CH2:26]Br)[CH:23]=[CH:22][C:21]=1[F:28])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:29])[C:20]1[CH:25]=[C:24]([CH2:26][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][CH:8]=3)[CH2:3][CH2:2]2)[CH:23]=[CH:22][C:21]=1[F:28])[CH3:17]
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CCOC(=O)c1cc(CBr)ccc1F
Product: CCOC(=O)c1cc(CN2CCC(c3c[nH]c4ccccc34)CC2)ccc1F
Yield: 78.9 %

Procedure:
This compound was prepared following the procedure described in example 1 (part D) starting with 0.2 g (1 mmol) of 3-piperidin-4-yl-1H-indole and 0.33 g (1.3 mmol 5-bromomethyl-2-fluoro-benzoic acid ethyl ester. After ionic exchange purfication, 0.30 g (79% of yield) of 2-fluoro-5-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid ethyl ester were obtained.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[F:5][C:6]([F:19])([F:18])[C:7]1[CH:16]=[C:15]2[C:10]([C:11](=O)[CH2:12][CH2:13][NH:14]2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:11]1[C:10]2[C:15](=[CH:16][C:7]([C:6]([F:19])([F:5])[F:18])=[CH:8][CH:9]=2)[NH:14][CH2:13][CH2:12]1
Reactant: CON
Reactant: O=C1CCNc2cc(C(F)(F)F)ccc21
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCNc2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methoxylamine hydrochloride (4.14 g, 49.5 mmol) was added to a solution of Example 16C (9.69 g, 45.0 mmol) in pyridine (40 mL), and mixture was stirred overnight at ambient temperature. Only one regioisomer, 7-(trifluoromethyl)-2,3-dihydroquinolin-4(1H)-one was converted to the oxime. The mixture was concentrated under reduced pressure and ethyl acetate (300 mL) was added. The organic layer was washed twice with water (300 mL) and brine, dried over sodium sulfate, and concentrate under reduced pressure. The residue was chromatographed on silica gel eluting with 20-70% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.70 (t, J=6.61 Hz, 2H), 3.19 (td, J=6.53, 1.86 Hz, 2H), 3.90 (s, 3H), 6.57 (s, 1H), 6.82 (dd, J=8.14, 1.70 Hz, 1H), 6.97 (s, 1H), 7.79 (d, J=8.14 Hz, 1H). MS (DCI) m/z 245.05 (M+H)+.
Reaction SMILES: [CH2:1]1[C:11]2[N:10]3[C:12]4[CH:21]=[CH:20][N:19]=[CH:18][C:13]=4[C:14]4[CH2:15][CH2:16][CH:17]=[C:8]([C:9]=43)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2]1.ClCCl.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>C(N(CC)CC)C>[CH2:1]1[C:11]2[N:10]3[C:12]4[CH:21]=[CH:20][N:19]=[CH:18][C:13]=4[C:14]4[CH2:15][CH2:16][CH:17]=[C:8]([C:9]=43)[CH:7]=[CH:6][C:5]=2[CH2:4][CH:3]([C:28]([CH:25]2[CH2:27][CH2:26]2)=[O:29])[CH2:2]1
Reactant: C1=CC2=C(CCCC2)n2c3c(c4cnccc42)CCC=C13
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)C1CCC2=C(C=CC3=CCCc4c3n2c2ccncc42)C1
Reaction time: 8 h

Procedure:
To a solution of 16.4 g. of the product of Example 1 in 500 ml. of dichloromethane, 7.3 g. of cyclopropanecarbonyl chloride is added, followed by dropwise addition of 10 ml. of triethylamine. A mildly exothermic reaction takes place, after which stirring of the mixture is continued at room temperature overnight. The mixture is then washed with 1N hydrochloric acid and water, and dried over anhydrous sodium carbonate. On evaporation to dryness, crude cyclopropyl 1,2,3,4,8,9-hexahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepin-3-yl ketone is obtained as a glassy product, m.p. 149°-152° on recrystallization from ethanol. A solution of 8.6 g. of this material in 120 ml. of tetrahydrofuran is added dropwise to a suspension of 2.3 g. of lithium aluminum hydride in 180 ml. of tetrahydrofuran. On completion of the addition, the mixture is first refluxed for 4 hours, then allowed to stir at room temperature overnight and finally decomposed in the usual manner. After filtering off the inorganic salts, the filtrate is dried over anhydrous sodium carbonate, evaporated in vacuo; the residue is dissolved in a 1:1 mixture of ethyl acetate-benzene and chromatographed on a 14 × 2.2 cm. column of basic alumina, activity I. The eluate is taken down to dryness; the residual oil dissolved in absolute alcohol, saturated with ethanolic hydrogen chloride, and once again evaporated to dryness. Upon crystallization of the residue from acetone, 3-(cyclopropylmethyl)-1,2,3,4,8,9-hexahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine hydrochloride, m.p. 267°, is obtained.
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.[Cl:6][C:7]1[C:8](I)=[N:9][CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1>C(#N)C>[Cl:6][C:7]1[C:8]([C:4]#[N:5])=[N:9][CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1
Reactant: N#C[Cu]C#N
Reactant: O=[N+]([O-])c1cnc(I)c(Cl)c1
Solvent: CC#N
Product: N#Cc1ncc([N+](=O)[O-])cc1Cl
Temperature: 80 °C
Reaction time: 5 h
Yield: 94.3 %

Procedure:
A suspension of copper cyanide (7 g) and 3-chloro-2-iodo-5-nitro-pyridine (7 g) in acetonitrile (200 mL) was heated to 80° C. within 1 hour and stirred at 80° C. for 5 hours. The solvent was evaporated and the residue was filtered in ethyl acetate over silicon dioxide gave 3-chloro-2-cyano-5-nitro-pyridine (4.26 g).