Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22]OS(C)(=O)=O)[O:19][C:18]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[C:10](=[O:16])[CH2:9]1.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[N:29]([CH2:22][C@@H:20]1[O:19][C:18](=[O:28])[N:17]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[C:10](=[O:16])[CH2:9]3)=[C:2]([F:1])[CH:3]=2)[CH2:21]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CCN1CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1=O
Temperature: 80 °C
Yield: 93.8 %

Procedure:
(5R)-3-(3-Fluoro-4-{4-ethyl-3-oxopiperazin-1-yl}phenyl)-5-(methanesulfonyloxymethyl)-oxazolidin-2-one (950 mg) was dissolved in dry DMF (30 ml) and sodium azide (893 mg) was added. The mixture was heated at 80° C. for 5 hours, and then evaporated to dryness. The residue was dissolved in ethyl acetate and the resulting solution washed with water and dried (MgSO4). The crude product so obtained was chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 6% methanol in dichloromethane. Relevant fractions were combined and evaporated to give (5R)-5-azidomethyl-3-(3-fluoro-4-{4-ethyl-3-oxopiperazin-1-yl}phenyl)oxazolidin-2-one (777 mg).
Reaction SMILES: CN(OC)C(=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH3:12])[CH:5]=1.[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1([Mg]Br)C=CC=CC=1.CCOCC>C1COCC1>[CH3:12][C:6]1[CH:5]=[CH:4][C:9]([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:23])=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: O=C(O)c1ccccc1
Reactant: COc1ccc(C(=O)N(C)OC)cc1C
Agent: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C(=O)c2ccccc2)ccc1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
N,3-dimethyl-N,4-bis(methyloxy)benzamide (Prepared from the corresponding benzoic acid following the standard literature procedure for the formation of Weinreb amide, 6.2 g, 29.6 mmol) was dissolved in anhydrous THF (110 mL) under nitrogen and the solution was cooled to 0° C. A solution of 3 M phenyl magnesium bromide in ether (15.0 mL, 44.4 mmol) was then added drop-wise while maintaining an internal temperature of 0° C. to 5° C. The resulting mixture was stirred for 3 h at 0° C. to 5° C. then quenched with 5% aqueous HCl (150 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuuo to give 9.2 g of the crude 39 that was used without additional purification. 1H NMR (400 MHz, CDCl3): δ 2.13 (s, 3H), 3.92 (s, 3H), 6.91 (d, J=8.8 Hz, 1H), 7.40-7.62 (m, 5H), 7.64-7.70 (m, 1H), 7.73-7.79 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:22])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[N:40]1[CH:45]=[CH:44][C:43]([CH:46]=O)=[CH:42][CH:41]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)=[O:22])[CH2:5][N:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH2:46][C:43]1[CH:44]=[CH:45][N:40]=[CH:41][CH:42]=1
Reactant: O=Cc1ccncc1
Reactant: COC(=O)[C@H](CNCc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)[C@H](CN(Cc1ccncc1)Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
3-[(Biphenyl-4-ylmethyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (0.050 g, 0.093 mmol) prepared as per the above listed example 656 was subjected to reductive amination as per procedure E with 4-pyridine carbaldehyde (0.010 ml, 0.093 mmol) and sodium triacetoxyborohydride (0.039 gms, 0.186 mmol) to yield the corresponding 3-(Biphenyl-4-ylmethyl-pyridin-4-ylmethyl-amino)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was then hydrolyzed as per general procedure C to yield the title compound (0.040 g, 80%). 1H-NMR(400 MHz, DMSOd6): 3.3 (m, 2H), 4.001 (s, 4H), 5.18 (m, 1H), 7.62–7.75 (m, 8H), 7.8–7.93 (m, 4H), 8.17 (m, 4H), 8.27 (m, 4H), 8.77 (d, 2H), 9.1 (d, 1H), 8.7 (S, 1H); LC/MS (m/z): 610.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:11]=2)=[CH:4][C:3]=1[N+:31]([O-])=O.Cl[Sn]Cl>CO>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:11]=2)=[CH:4][C:3]=1[NH2:31]
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(Cl)c([N+](=O)[O-])c3)nc2-c2ccc3ncccc3c2)n1
Agent: Cl[Sn]Cl
Solvent: CO
Product: Cc1cccc(-c2[nH]c(Cc3ccc(Cl)c(N)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 71 %

Procedure:
To a suspension of 6-(2-(4-chloro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline (Example 74, prepared according to the method described in US 2008/0319012 A1) (50 mg, 0.110 mmol) in MeOH (2 mL) was added SnCl2 (104 mg, 0.548 mmol) and the mixture was stirred at 55° C. After 2.5 hours, the reaction mixture was cooled to room temperature, concentrated under reduced pressure. The residue was diluted with H2O (5 mL), filtered, and the filtrate was washed with 2N HCl (5 mL) and neutralized by addition of 5N NaOH solution to pH 7˜8. The precipitate was filtered, washed with H2O and Et2O, and dried under vacuum for overnight. The precipitate was purified by MPLC on silica gel (MeOH:EA:CH2Cl2=1:20:80 (v/v) to 1:4:16 (v/v)), and on NH silica gel (MC) to afford the title compound (33.1 mg, 71%). 1H NMR (300 MHz, CDCl3) δ 2.50 (3H, s), 4.09 (2H, s), 6.66 (1H, dd), 6.68 (1H, s), 6.96 (1H, d), 7.19 (1H, d), 7.25 (1H, bs), 7.36-7.39 (1H, m), 7.40 (1H, dd), 7.96 (1H, d), 8.10 (1H, d), 8.15-8.16 (2H, m), 8.91 (1H, dd). MS (ESI) m/z 426 (MH+).
Reaction SMILES: [OH:1][C@H:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:13]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.F[B-](F)(F)F.C[O+](C)C.O>C(Cl)Cl>[CH3:13][O:1][C@H:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9]
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: C[C@@H](O)CNC(=O)OC(C)(C)C
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: CO[C@H](C)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
To a solution of tert-butyl [(2R)-2-hydroxypropyl]carbamate (2.7 g) in CH2Cl2 (41 ml) were added N,N,N′,N′-tetramethylnaphthalene-1,8-diamine (3.63 g) and trimethyloxonium tetrafluoroborate (2.51 g), and the whole was stirred for 3 hours at room temperature. Water was added to the mixture, and the whole was extracted with EtOAc, and the extract was washed with water and brine and dried over MgSO4. Concentration under reduced pressure gave tert-butyl [(2R)-2-methoxypropyl]carbamate (2.73 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[NH2:16][C:17]1[S:18][CH:19]=[C:20]([Br:26])[C:21]=1[C:22]([O:24][CH3:25])=[O:23]>>[Br:26][C:20]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:17]([NH:16][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2=[O:1])[S:18][CH:19]=1
Reactant: COC(=O)c1c(Br)csc1N
Reactant: O=C(O)CN1C(=O)CCc2ccccc21
Product: COC(=O)c1c(Br)csc1NC(=O)CN1C(=O)CCc2ccccc21

Procedure:
The title compound was prepared from 2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid (447 mg, 2.18 mmol) and methyl 2-amino-4-bromothiophene-3-carboxylate (516 mg, 2.18 mmol) according to protocol A. Retention time (min)=2.528, method [1], MS(ESI) 423.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][N:10]1[C:14]([CH3:15])=[C:13]([C:16](O)=[O:17])[C:12](=[O:19])[N:11]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O.CCOC(C)=O>[OH:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:16]([C:13]2[C:12](=[O:19])[N:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:10]([CH3:9])[C:14]=2[CH3:15])=[O:17])=[N:7][CH:6]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1ccc(O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(O)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To a suspension of 6-aminopyridin-3-ol (330 mg, 3 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (710 mg, 306 mmol) in DMF (10 mL) was added EDCI (690 mg, 3.6 mmol) and HOAT (80 mg, 0.6 mmol). The reaction was stirred at 60° C. for 4 hours, then cooled to rt and diluted with water (100 mL) and EtOAc (2 mL). The mixture was cooled to 0° C. and stirred overnight. The resulted solid was collected through filtration to give title compound as a light brown solid (680 mg, 70%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[CH3:9][C:10]1[C:11]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=3)=[O:24])[CH2:19][CH2:18]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1>>[CH3:9][C:10]1[C:11]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([N:7]4[C@@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]4=[O:8])=[CH:27][CH:26]=3)=[O:24])[CH2:21][CH2:22]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: O=C1CC[C@H](CO)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@@H]4CO)cc3)CC2)c(C)c1
Yield: 47.6 %

Procedure:
Using (R)-5-hydroxymethylpyrrolidin-2-one (137 mg) and [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (500 mg) described in Preparation Example 113 and by the reaction and treatment in the same manner as in Example 1, the title compound (231 mg) was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[CH3:7][C:8]([CH3:10])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1>[CH:8]([NH:6][C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)([CH3:10])[CH3:7]
Reactant: Nc1cc[nH]n1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)Nc1cc[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a mixture of 1H-pyrazol-3-ylamine (8.3 g, 100 mmol), acetone (7.4 mL, 100 mmol) and acetic acid (12 mL, 200 mmol) in THF (280 mL) was added, in portions, sodium triacetoxyborohydride (27 g, 120 mmol) while cooling with an ice-water bath. The mixture was stirred at room temperature for 1 h and then at 50° C. for 3 h. After cooling to room temperature, 10 N NaOH (40 mL) was added dropwise, and stirred gently for 1 h. The clear solution was isolated with decantation. The gummy residue was washed with THF (2×50 mL). All the THF solutions were combined and concentrated. The residue was purified by silica gel column chromatography (EtOAc), affording isopropyl-(1H-pyrazol-3-yl)-amine (8.5 g, 68%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.34 (d, 1H), 5.62 (d, 1H), 3.58 (m, 1H), 1.22 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][C:27]([NH:29][NH2:30])=[O:28])[CH2:24][C:23]([CH3:32])([CH3:31])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[C:33](O)(=O)C.C(N)=N.CC(O)=O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([N:26]4[CH:33]=[N:30][NH:29][C:27]4=[O:28])[CH2:24][C:23]([CH3:32])([CH3:31])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1
Reactant: CC1(C)CC(NC(=O)NN)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Reactant: CC(=O)O
Agent: N=CN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CC(n2cn[nH]c2=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product of Step B (0.14 mmol) and formamidine acetate (72 mg, 0.70 mmol) in 5.0 mL of DMF was allowed to stir at rt for 2 h. AcOH (40 μL, 0.70 mmol) was then added. The resulting mixture was stirred at 80° C. for 16 h. After cooling to rt, the reaction mixture was diluted with EtOAc (20 mL) and washed with brine (3×20 mL). The organic phase was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+S cartridges using 1:99 v/v CH3OH/CH2Cl2 as the eluant afforded the title compound: 1H NMR δ 1.53 (s, 3H), 1.62 (s, 3H), 2.18 (t, J=12.7, 1H), 2.36 (dd, J=6.3, 13.1, 1H), 5.56 (m, 1H), 6.95 (d, J=8.3, 2H), 7.16-7.38 (m, 7H), 10.1 (br. s, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[NH:6][C@@H:5]([CH:7]=[O:8])[CH2:4][CH2:3]1.[C:9]([Si](C)(C)C)([F:12])([F:11])[F:10]>>[F:10][C:9]([F:12])([F:11])[CH:7]([C@H:5]1[CH2:4][CH2:3][C@@H:2]([CH3:1])[NH:6]1)[OH:8]
Reactant: C[C@@H]1CC[C@H](C=O)N1
Reactant: C[Si](C)(C)C(F)(F)F
Product: C[C@@H]1CC[C@H](C(O)C(F)(F)F)N1

Procedure:
2,2,2-trifluoro-1-((2R,5R)-5-methylpyrrolidin-2-yl)ethanol (Compound 2, Scheme I, R3=methyl) is prepared by oxidation of ((2R,5R)-5-methylpyrrolidin-2-yl)methanol (Compound 4, Scheme I, R3=methyl) to afford the resulting aldehyde, (2R,5R)-5-methylpyrrolidine-2-carbaldehyde (see e.g., Smith et al., March's Advanced Organic Chemistry, 6th ed., Wiley, N.J., 2007, p. 1715-1728). The resulting aldehyde is reacted with CF3-TMS (trimethyl(trifluoromethyl)silane) to afford 2,2,2-trifluoro-1-((2R,5R)-5-methylpyrrolidin-2-yl)ethanol (see e.g., Prakash et al., J. Am. Chem. Soc. 111: 393, 1989).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:35]1([CH2:38][S:39](Cl)(=[O:41])=[O:40])[CH2:37][CH2:36]1>ClCCl>[CH2:13]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:39]([CH2:38][CH:35]3[CH2:37][CH2:36]3)(=[O:41])=[O:40])[CH:12]=2)[CH2:7][CH2:8][CH:9]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)CC1CC1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCc2ccc(CNS(=O)(=O)CC3CC3)cc2C1Cc1ccccc1
Reaction time: 8 h
Yield: 75.7 %

Procedure:
tert-Butyl 7-(aminomethyl)-1-benzyl-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.600 g, 1.637 mmol) was suspended in dichloromethane (5 mL) and triethylamine (0.228 mL, 1.637 mmol) and cooled to 0° C. Cyclopropylmethanesulfonyl chloride (0.253 g, 1.637 mmol) was added. The solid immediately dissolved. The mixture was stirred overnight and then diluted with dichloromethane and washed with brine (3×50 mL). The organic extract was collected dried on MgSO4 and evaporated under reduced pressure. The residue was purified by flash-chromatography on silica gel (100% dichloromethane 5 minutes then gradient to 1% MeOH in dichloromethane). Product was isolated as white powder (601.9 mg, 1.24 mmol, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N+](C1C=CC(C#N)=CC=1)([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)cc1
Agent: N#Cc1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [H-]
Product: NCc1ccc(N)cc1
Yield: 37 %

Procedure:
A process wherein p-aminobenzonitrile derived from p-nitrobenzonitrile is reduced with lithium aluminum hydride to obtain p-aminobenzylamine (yield: 37%) (N.C. Brown et al, J. Medicinal Chem., 20, 1189 (1977)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C:19]([C@@H:21]([OH:28])[C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](=[O:28])[C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:16][CH2:15]4)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)CC2([C@@H](O)c2ccccn2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2ccccn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
A solution of (R)-tert-butyl 1-(4-fluorophenyl)-4a-(R/S)-(hydroxy(pyridin-2-yl)methyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (410 mg, 0.86 mmol) in dry dichloromethane (10 mL) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (547 mg, 1.29 mmol; Dess-Martin periodinane) and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was cooled and treated with saturated sodium hydrogen carbonate solution (20 mL) followed by dichloromethane (10 mL). The mixture was stirred for 10 minutes and the phases were separated. The aqueous phase was extracted with further dichloromethane (×2) and the combined organic phases dried over sodium sulfate. The solids were removed by filtration, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (gradient: 20-40% ethyl acetate in cyclohexane) to afford (R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate as a pale yellow foam (185 mg). LCMS (Method B, ESI): RT 4.13 min, m+H=475.5; 1H NMR (400 MHz, CDCl3): δ 8.68 (d, J=4.8 Hz, 2 H); 7.44-7.45 (m, 5 H); 7.15-7.16 (m, 3 H); 6.51 (s, 2 H); 2.83 (br s, 5 H); 2.49 (s, 1H); 1.43 (s, 9 H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:17]=[C:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][C:27]([NH2:29])=[O:28])[C:15]([C:30]([F:33])([F:32])[F:31])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:36][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12]3[N:17]=[C:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][C:27]([NH2:29])=[O:28])[C:15]([C:30]([F:32])([F:33])[F:31])=[CH:14][N:13]=3)[CH:6]=2)[CH2:1]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc3c(c2)CCNC3)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCc2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)ccc2C1
Reaction time: 0.08 h
Yield: 88.3 %

Procedure:
2-(2-(2-(2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (21) (25 mg, 0.055 mmol) was suspended in methanol (2 mL) and 37% aqueous formaldehyde (0.016 mL, 0.22 mmol) was added. The mixture was stirred for five minutes then sodium tri(acetoxy)borohydride (58 mg, 0.27 mmol) was added. After stirring for 2 hours at room temperature the mixture was concentrated and the residue treated with 10% aqueous NaOH (1 mL) for five minutes. Brine (2 mL) was added, and the mixture was extracted with ethyl acetate (5×5 mL). The combined ethyl acetate extracts were washed with brine, dried (sodium sulphate) and evaporated to give the title compound (28) (22.8 mg, 88% yield) as an off-white solid; 1H NMR (400 MHz, d4-MeOD) δ 8.54 (d, J=0.5 Hz, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.47 (dd, J=8.3, 2.2 Hz, 1H), 7.28-7.16 (m, 4H), 7.04 (d, J=8.3 Hz, 1H), 3.66 (s, 2H), 3.60 (s, 2H), 3.21-3.11 (m, 2H), 3.11-3.02 (m, 2H), 2.96 (t, J=6.0 Hz, 2H), 2.76 (t, J=6.1 Hz, 2H), 2.46 (s, 3H). LCMS Method C: rt 4.78 min; m/z 470.1 [M+H]+; m/z 468.1 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH2:12])[C:3]=1[NH:13][CH3:14].[CH2:15]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=O)[CH3:16].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[Br:1][C:2]1[C:3]2[N:13]([CH3:14])[C:20]([C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[S:17][CH2:15][CH3:16])=[N:12][C:4]=2[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CNc1c(N)cc(C(F)(F)F)cc1Br
Reactant: CCSc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cc(Br)c2n1C
Temperature: 115 °C
Yield: 43.2 %

Procedure:
A mixture of 3-bromo-N2-methyl-5-trifluoromethylbenzene-1,2-diamine (2.22 g), 2-ethylsulfanylbenzoic acid (1.80 g), WSC (1.40 g), and pyridine (10 ml) was stirred under reflux at 115° C. for 6 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 1.48 g of 7-bromo-2-(2-ethylsulfanylphenyl)-1-methyl-5-trifluoromethyl-1H-benzimidazole (hereinafter referred to as Present Compound 74).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[C:12](/[CH3:25])=[CH:13]/[C:14]3[CH:24]=[CH:23][C:17]([C:18](OCC)=[O:19])=[CH:16][CH:15]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C.CO.O>CCOCC>[CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[C:9](/[C:12](/[CH3:25])=[CH:13]/[C:14]3[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:23][CH:24]=3)[CH:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCO3)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: C/C(=C\c1ccc(CO)cc1)c1ccc2c(c1)C(C)(C)CCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
4.0 g of ethyl p-[(E)-2-(4,4-dimethyl-6-chromanyl)propenyl]benzoate were dissolved in 50 ml of ether and the solution was treated slowly at 0° C. with 25.2 ml of a diisobutylaluminium hydride solution (20% in toluene). After stirring at 0° C. for 1 hour, 25 ml of methanol/water (1:1) were cautiously added dropwise thereto, the mixture was stirred at room temperature for 30 minutes and the precipitate was filtered off. The filtrate was dried, filtered over a short column of silica gel [eluting agent: hexane/ether (1:1)] and evaporated. After recrystallization from hexane/ether, there was obtained 2.9 g of p-[(E)-2-(3,4-dihydro-4,4-dimethyl-1-benzopyran-6-yl)propenyl]benzyl alcohol in the form of colorless crystals of melting point 80°-81° C.
Reaction SMILES: [ClH:1].C(O[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:9][CH:8]=1)=[NH:6])C.[NH3:34].C(O)C>>[ClH:1].[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:9][CH:8]=1)(=[NH:34])[NH2:6]
Reactant: N
Reactant: CCOC(=N)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=N)N)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-[4-(ethoxycarbonimidoyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide hydrochloride (364 mg) was added a solution of 14% ammonia/ethanol (5 ml). The resulting mixture was stirred at room temperature overnight and then at 50° C. for 3 hours. The reaction mixture was concentrated, the residue was suspended in ethyl acetate and 4 N hydrochloric acid/ethyl acetate was added. The precipitate was collected by filtration, was washed with ethyl acetate and further was recrystallized from acetonitrile/methanol/ethyl acetate to obtain N-(4-amidinophenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide hydrochloride (compound 42) (127 mg) as colorless crystals.