Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[C:33]1([C@H:39](O)[CH3:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][C@@H:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:40])=[O:13])(=[O:7])=[O:6]
Reactant: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Reactant: C[C@@H](O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CO[C@@H](C(=O)O[C@H](C)c2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 68.2 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (13) (0.50 g, 1.2 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 0.7 mL (1.4 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 0.28 mL of (R)-(+)-1-phenylethanol (0.40 g, 3.3 mmol) and 0.28 mL of pyridine (0.26 g, 3.3 mmol) in 10 mL of anhydrous dichloromethane was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:2) to provide 0.42 g (67% yield) of the title compound (34a) as a colorless oil. Rf=0.54 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=0.98 (s, 3H), 0.99 (s, 3H), 1.61 (d, J=6.4 Hz, 3H), 2.23-2.30 (m, 2H), 3.18-3.22 (m, 2H), 3.63-3.66 (m, 2H), 3.81-3.82 (m, 4H), 3.92 (d, J=9.2 Hz, 1H), 4.19 (d, J=9.2 Hz, 1H), 4.26 (d, J=11.2 Hz, 1H), 4.49 (d, J=11.2 Hz, 1H), 6.01 (q, J=6.4 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.35-7.39 (m, 5H) ppm. D.e.>98% (by 1H NMR-spectroscopy, 400 MHz, CDCl3). MS (ESI) m/z 535.18 (M+Na)+. The analytical data was consistant with the proposed structure.
Reaction SMILES: [Br:1]Br.N[C:4]1[CH:5]=[C:6]2[CH2:14][O:13][C:12]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=3[C:10](=[C:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:7]2=[N:8][CH:9]=1.N([O-])=O.[Na+].[OH-].[NH4+]>Br.O>[Br:1][C:4]1[CH:5]=[C:6]2[CH2:14][O:13][C:12]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=3[C:10](=[C:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:7]2=[N:8][CH:9]=1
Reactant: BrBr
Reactant: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3OCc3cc(N)cnc32)CC1
Agent: Br
Agent: O=N[O-]
Agent: [NH4+]
Solvent: O
Product: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3OCc3cc(Br)cnc32)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
Bromine (1.0 ml, 19.4 mmol) was added to a suspension of ethyl 4-(3-amino-8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)-1-piperidine-carboxylate (1.5 g, 3.75 mmol) in hydrobromic acid (150 ml) at 0° C. for 10 minutes. Sodium nitrite (0.7 g, 10.14 mmol) in water (5 ml) was added at 0° C., and the mixture was stirred at 0° C. for 1 hour and then at 20° C. for 2 hours. The reaction mixture was poured onto ice (200 g), basified with concentrated ammonium hydroxide and extracted with ethyl acetate (500 ml). The organic layer was washed with water (300 ml), dried (MgSO4), filtered and evaporated, yielding a crude product which was chromatographed on silica gel and eluted with 30%ethylacetate/hexanes. The product was recrystallized from ether to afford a white powder, ethyl 4-(3-bromo-8-chloro-5,11-dihydro[1]benz-oxepino[4,3-b]pyridin-11-ylidene)-1-piperidine-carboxylate (1.0 g, 58%), m.p. 148-149° C. MS (CI, M+H)=463; anal.: found: C, 53.92; H, 4.16; N, 6.18; C21H20BrClN2O3 requires: C, 54.38; H, 4.34; N, 6.04.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([N:8]2[CH2:24][CH2:23][C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:18]=[N:19][CH:20]=[N:21][CH:22]=4)[N:14]=[CH:15][C:10]=3[CH2:9]2)[CH:7]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:25][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=2)=[CH:7][C:6]=1[N:8]1[CH2:24][CH2:23][C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)[N:14]=[CH:15][C:10]=2[CH2:9]1
Reactant: Cc1ccc(N)cc1N1CCc2nc(Nc3cncnc3)ncc2C1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N1CCc2nc(Nc3cncnc3)ncc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
To a solution of [6-(5-Amino-2-methyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-pyrimidin-5-yl-amine (50.0 mg, 0.15 mmol), 3-Trifluoromethylbenzoic acid (28.5 mg, 0.15 mmol), and DIPEA (78 μl, 0.45 mmol) in DMF was added HATU (59 mg, 0.15 mmol), and the reaction mixture was stirred for 3 hour at room temperature. The reaction mixture is diluted with ethyl acetate and washed with 5% aqueous sodium bisulphate solution, saturated aqueous sodium bicarbonate solution and brine. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (SiO2, 2-10% methanol in chloroform) to give 49.75 mg (65.6%) of N-{4-Methyl-3-[2-(pyrimidin-5-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-phenyl}-3-trifluoromethyl benzamide [17] as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10](OC(C)(C)C)=[O:11])[CH2:7][N:6]1[C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:21])[CH3:20])=[O:4].Cl.[CH:29](N(C(C)C)CC)(C)C.C(OC(=O)C)(=O)C>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10](=[O:11])[CH3:29])[CH2:7][N:6]1[C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:21])[CH3:20])=[O:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1C(=O)OC)C(C)C
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CN(C(C)=O)CC1C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
3-(2-Methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (465 mg, 1.2 mmol) was dissolved in dichloromethane (1 mL) and HCl (4M dioxane, 3 mL) was added. The resultant suspension was stirred at room temperature for 30 minutes, after which all volatiles were removed in vacuo. The crude material was dissolved in THF and diisopropyl ethylamine (154 mg, 1.2 mmol) was added, followed by acetic anhydride (122 mg, 1.2 mmol). The reaction was stirred at room temperature. After 30 minutes, all volatiles were removed in vacuo. The crude material was purified by silica gel chromatography (eluent: DCM/MeOH) to yield the product 1-Acetyl-3-(2-methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-4-carboxylic acid methyl ester (273 mg, 0.829 mmol): LCMS-ESI+: calc'd for C14H23N3O6: 329.4 (M+). Found: 330.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][O:15][C:16](=[O:27])[C@H:17]([CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:20])[NH2:18]>>[CH3:14][O:15][C:16](=[O:27])[CH:17]([NH:18][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[CH:19]([OH:20])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)[C@@H](N)C(O)c1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Product: COC(=O)C(NC(=O)c1cc2cc(Cl)ccc2[nH]1)C(O)c1ccccc1

Procedure:
From 5chloro-1H-indole-2-carboxylic acid and (+)-threo b-phenylserine methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH2:13])=[O:12])[N:3]=1.I.[F:15][C:16]([F:24])([F:23])[CH2:17][NH:18][C:19](=[NH:22])SC.C(Cl)(Cl)Cl.CO.N>>[F:15][C:16]([F:24])([F:23])[CH2:17][N:18]=[C:19]([NH2:22])[NH:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH2:13])=[O:12])[N:3]=1
Reactant: CSC(=N)NCC(F)(F)F
Reactant: NC(=O)CCCCn1ccc(N)n1
Agent: I
Agent: N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC(=O)CCCCn1ccc(NC(N)=NCC(F)(F)F)n1

Procedure:
A mixture of 5-(3-aminopyrazol-1-yl)valeramide (18.2 mg.) and (2,2,2-trifluoroethyl)-S-methylisothiourea hydroiodide (51 mg.) was heated at 100° for 20 minutes. Preparative high pressure liquid chromatography on silica gel, using CHCl3 /MeOH/ammonia (s.g. 0.880) 8:2:0.5 v/v/v as eluant gave 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeramide, m.p. 129°-130° (40%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:41])[CH:20]([NH:32][C:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:34])[CH2:21][S:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:24])=[O:23])[CH:13]([OH:42])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:41])[CH:20]([NH:32][C:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:34])[CH2:21][S:22]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:23])[C:13](=[O:42])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCCN(C(=O)OCc2ccccc2)CC1O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CN(C(=O)OCc2ccccc2)CCCC1NC(=O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
3-Hydroxy-4-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionylamino}-azepane-1-carboxylic acid benzyl ester (100 mg, 0.167 mmol) was dissolved in DMSO (5 mL). Triethylamine (0.3 mL) and then SO3 pyridine complex (150 mg) were added and the mixture was stirred at ambient temperature for 3 hours. After dilution with ethyl acetate (100 mL), the solution was washed with water (50 mL) and brine, dried with MgSO4 and evaporated under vacuum. The residue was purified by flash chromatography on silica gel (Eluent: 5% methanol in ethyl acetate) to yield 4-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionylamino}-3-oxo-azepane-1-carboxylic acid benzyl ester (75 mg); 1H NMR: (DMSO) 8.23–8.08 (m, 1H), 7.40–7.29 (m, 10H), 7.06–6.98 (m, 1H), 5.20–5.09 (m, 2H), 4.79–4.65 (m, 1), 4.52–4.31 (m, 3H), 4.02–3.80 (m, 2H), 3.62–3.23 (m, 11H), 3.00–2.78 (m, 1H), 1.88–1.55 (m, 4H); MS: (M+H)+ 601.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@@H:6]([CH2:15][CH3:16])[N:5]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4]=2[N:3]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(O)CCC>[CH:17]1([N:5]2[C:4]3[N:3]=[C:2]([NH:25][CH:22]4[CH2:24][CH2:23]4)[N:11]=[CH:10][C:9]=3[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@H:6]2[CH2:15][CH3:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CC1
Reactant: CC[C@@H]1c2nncn2-c2cnc(Cl)nc2N1C1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@@H]1c2nncn2-c2cnc(NC3CC3)nc2N1C1CCCC1

Procedure:
(R)-7-chloro-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine (70 mg, 0.23 mmol), cyclopropylamine (0.5 ml, 7.18 mmol), DIPEA (0.16 ml, 0.918 mmol) in nBuOH (2 ml) were heated in a sealed tube in the microwave at 140° C. for 90 minutes. The reaction mixture was concentrated in vacuo, and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 □M, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] to afford the title compound as an off-white powder. The free base was generated using a bicarbonate resin, and was freeze-dried to give the title compound as a colourless solid (25.6 mg, 34% yield)
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])[CH2:23][CH2:22][C:21]([C:34]([O:36]C)=[O:35])=[CH:20][C:19]=3[CH:38]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])[CH2:23][CH2:22][C:21]([C:34]([OH:36])=[O:35])=[CH:20][C:19]=3[CH:38]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.6 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(2-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (391 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 1 day. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (257 mg) as yellow crystals.
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]([Cl:18])([Cl:17])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[S:15]Cl.[Cl-].[K+]>C(O)(=O)C.C(OCC)C>[Cl:4][C:5]([Cl:18])([Cl:17])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[S:15][C:1]#[N:2]
Reactant: [C-]#N
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: N#CSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Temperature: 10 °C
Reaction time: 5 h
Yield: 89.2 %

Procedure:
At 10° to 15° C., 13 g of potassium cyanide is dissolved in 100 ml of glacial acetic acid. At 10° C., a solution of 61.4 g of 2-trichloromethyl-4-nitrobenzenesulfenic acid chloride in 200 ml of diethyl ether is added to the solution. The mixture is stirred for 2 hours at 10° C. and for 5 hours at room temperature. The precipitated potassium chloride is filtred off, the solvent is distilled off, and the residue is recyrstallized from petroleum ether. There is obtained 53 g (89% of theory) of 2-trichloromethyl-4-nitrophenyl thiocyanate; m.p.: 72° C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@@H:11]1[C@H:17]([N:18](CC2C=CC=CC=2)CC2C=CC=CC=2)[C:16](=[O:33])[NH:15][C:14]2[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:13]=2[O:12]1)C1C=CC=CC=1>CO.[Pd]>[NH2:18][C@@H:17]1[C:16](=[O:33])[NH:15][C:14]2[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:13]=2[O:12][C@@H:11]1[CH2:10][CH2:9][OH:8]
Reactant: O=C1Nc2cc(F)ccc2O[C@H](CCOCc2ccccc2)[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1C(=O)Nc2cc(F)ccc2O[C@@H]1CCO
Yield: 96 %

Procedure:
The title compound was prepared in 96% yield by hydrogenation of (6R,7S)-6-(2-benzyloxy-ethyl)-7-dibenzylamino-2-fluoro-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in methanol with Pd/C (10%), MS m/e (%): 241.3 (M+H+, 100).
Reaction SMILES: [CH:1]1([CH:7]([O:35][CH3:36])[C:8]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:9]=2[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:37]#[C:38]Br.C(#N)C>CO>[CH:1]1([CH:7]([O:35][CH3:36])[C:8]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:9]=2[CH2:10][N:11]([CH2:12][C:13]2[CH:14]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=2)[C:38]#[N:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCCC1
Reactant: N#CBr
Solvent: CC#N
Solvent: CO
Product: COC(c1ccc(C(F)(F)F)cc1CN(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of N-(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)(3,5-bis(trifluoromethyl)phenyl)methanamine (150 mg, 0.28 mmol) and NaOAc.3H2O (77.6 mg, 0.57 mmol) in methanol was added cyanogen bromide in acetonitrile (5.0 M, 0.1 mL, 0.5 mmol). The slurry was stirred at room temperature overnight. The mixture was loaded onto a samplet and purified by chromatography over 25+S Biotage silica column (eluted with 0-30% ethyl acetate in heptane) to afford the title compound (144.1 mg, 92%). 1H NMR (400 MHz, CDCl3) δ ppm 0.91-1.19 (m, 6H) 1.41-1.53 (m, 1H) 1.62 (d, J=7.88 Hz, 2H) 1.71-1.79 (m, 1H) 1.96 (d, J=12.45 Hz, 1H) 3.16 (s, 3H) 4.00 (d, J=7.47 Hz, 1H) 4.32 (d, J=14.11 Hz, 1H) 4.32 (s, 2H) 4.40 (d, J=14.11 Hz, 1H) 7.50 (d, J=8.30 Hz, 1H) 7.54 (s, 1H) 7.63 (d, J=8.30 Hz, 1H) 7.78 (s, 2H) 7.91 (s, 1H). MS (ES−) Calc: 552.2, Found: 551.5 (M−1).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:11][OH:12].N1C=CC=CC=1>CCO>[C:1]1([CH2:7][CH:8]=[N:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=CCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31 %

Procedure:
Phenylacetaldehyde (12.0 g, 7.8 ml, 0.1 mol) was dissolved in EtOH (360 ml) and mixed while stirring successively with hydroxylamine hydrochloride (10.4 g, 0.15 mol) and abs. pyridine (9.7 ml, 0.12 mol). After stirring for 1.5 h at RT, the reaction mixture was concentrated, the residue taken up in toluene (1×100 ml) and the solvent removed again under vacuum. The oily residue was stirred with EtOAc (350 ml) and water (90 ml) for 15 min. Subsequently, the phases were separated. The organic phase was washed with water (2×80 ml), dried and concentrated. The oil obtained crystallised after a short time. The oil was recrystallised from n-hexane (20 ml). Compound V was obtained as a white solid in a yield of 31% (4.13 g) having a melting point of 90-94° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:16][CH:17]1[N:20]([CH2:21][C:22](=[O:31])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19](=[O:32])[CH2:18]1)[CH2:13][CH2:14][CH3:15].C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>ClCCl.CCOCC>[CH2:12]([S:16]([CH:17]1[N:20]([CH2:21][C:22](=[O:31])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19](=[O:32])[CH2:18]1)=[O:9])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCSC1CC(=O)N1CC(=O)CCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCS(=O)C1CC(=O)N1CC(=O)CCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of m-chloroperbenzoic acid (0.81 g, 0.0047 moles) in dichloromethane (50 ml) was added dropwise to a stirred solution of 4-butylthio-N-(4-phenyl-2-oxobutyl)azetidin-2-one (1.2 g, 0.0039 moles) in dichloromethane (50 ml) at -60° C. Stirring continued at -60° C. for 30 minutes then the mixture was poured into an aqueous solution of sodium hydrogen carbonate and sodium sulphite. The layers were separated and the aqueous was extracted with dichloromethane. The combined extracts were dried and evaporated to give a solid which was slurried in ether, filtered, washed with ether and petrol. The solid was recrystallised from ether to give the title compound as white crystals, 280 mg (22%), mp 145-6° C.
Reaction SMILES: [H][H].[N:3]1[C:8]2[NH:9][CH:10]=[CH:11][C:7]=2[C:6]([N:12]2[CH2:16][CH2:15][C@@H:14]([N:17]([CH3:25])[C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[CH2:13]2)=[N:5][CH:4]=1>CO.[Pd]>[N:3]1[C:8]2[NH:9][CH:10]=[CH:11][C:7]=2[C:6]([N:12]2[CH2:16][CH2:15][C@@H:14]([N:17]([CH3:25])[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)[CH2:13]2)=[N:5][CH:4]=1
Reactant: CN(c1ccnc(Cl)n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(c1ccncn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1

Procedure:
Under the atmosphere of hydrogen, a mixture of (R)—N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-chloro-N-methylpyrimidin-4-amine (30 mg, 0.09 mmol), Pd/C (10 wt. %, 20.0 mg) was stirred in 3.0 mL methanol at ambient temperature for 4 h. The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by preparative TLC (DCM/MeOH=15/1) to give the title compound. MS (m/z): 296 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[N:21]=[N:22][N:23]([CH2:28][C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=3)[C:24]=2[N:25]([CH3:27])[CH3:26])=[N:8][N:7]=1)C.[Li+].[BH4-].[NH4+].[Cl-]>C1COCC1>[F:37][C:35]([F:36])([F:38])[C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([C:39]([F:42])([F:40])[F:41])[CH:32]=1)[CH2:28][N:23]1[C:24]([N:25]([CH3:26])[CH3:27])=[C:20]([C:9]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:6]([CH2:5][CH2:4][OH:3])=[N:7][N:8]=2)[N:21]=[N:22]1
Reactant: CCOC(=O)Cc1nnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2N(C)C)n1Cc1ccc(F)cc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)c1c(-c2nnc(CCO)n2Cc2ccccc2Cl)nnn1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
Dissolve [5-[1-(3,5-bis-trifluoromethyl-benzyl)-5-dimethylamino-1H-[1,2,3]triazol-4-yl]-4-(2-chloro-4-fluoro-benzyl)-4H-[1,2,4]triazol-3-yl]-acetic acid ethyl ester (338 mg) in THF (5 mL). Cool to 0° C., add 2M LiBH4 (0.8 mL, 2M soln in THF) and stir overnight while slowly warming to RT. Pour reaction into aqueous NH4Cl (15 mL) and extract with EtOAc (2×15 mL). Purify via radial chromatography using a gradient of 1:1 to 1:5 hexanes:EtOAc to give the title compound (137 mg, 44%). MS (IS) 592.0 (M+1); Rf=0.11 (1:5 hexanes:EtOAc).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([NH2:13])=O)[NH:6]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:11][NH2:13])[NH:6]2
Reactant: NC(=O)c1cc2c(F)cccc2[nH]1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCc1cc2c(F)cccc2[nH]1
Temperature: 80 °C
Yield: 33.4 %

Procedure:
To a solution of 36 (130 mg, 0.730 mmol) in anhydrous THF (5.0 mL) was added LiAlH4 (138 mg, 3.65 mmol) at 0-5° C. The reaction mixture was heated at 80° C. overnight. After cooling to RT, the mixture was treated with aq. Na2SO4. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried and concentrated. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc/TEA (10:10:0.5) to afford 40 mg (33%) of (4-fluoro-1H-indol-2-yl)methanamine (38) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 11.22 (s, 1H), 7.14 (d, J=8.0 Hz, 1H), 6.97 (m, 1H), 6.70 (m, 1H), 6.28 (s, 1H), 3.82 (s, 2H). LCMS (ESI) m/z: 148.1 [M+H−17]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([F:17])=[C:7](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])[C:8](Cl)=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(N(CC)CC)C>[C].[Pd].CO>[C:1]([NH:4][C:5]1[C:6]([F:17])=[C:7]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Cl)c(/C=C/C(=O)O)c1F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)Nc1cccc(CCC(=O)O)c1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
As presented in the following reaction formula, a mixture of (E)-3-(3-acetamido-6-chloro-2-fluorophenyl)acrylic acid (15 g, 0.058 mol), palladium carbon (Pd/C; 1.5 g, 5.8 mmol), methanol (100 mL) and triethylamine (6.4 g, 0.06 mol) was stirred under 1 atm (H2) at 50° C. overnight. The mixture was filtered and concentrated to give 3-(3-acetamido-2-fluorophenyl)propanoic acid (10 g, yield: 73%) as a yellow solid.