Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[CH:8][CH:7]=1)=O.[OH-].[Li+]>CO.O>[C:22]1([S:19]([N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][C:9]3[CH:8]=[CH:7][C:6]([NH2:5])=[CH:11][CH:10]=3)[CH2:14][CH2:15]2)(=[O:20])=[O:21])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc(CC2CCN(S(=O)(=O)c3ccccc3)CC2)cc1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(CC2CCN(S(=O)(=O)c3ccccc3)CC2)cc1
Reaction time: 48 h
Yield: 83.2 %

Procedure:
A mixture of 2,2,2-trifluoro-N-[4-(1-benzenesulfonylpiperidin-4-ylmethyl)-phenyl]acetamide (0.45 g) and lithium hydroxide (0.23 g) in methanol (10 mL) and water (1 mL) was stirred for about 48 hours. The reaction mixture was concentrated in vacuo, diluted with cold water, and extracted with dichloromethane. The organic layer was washed with cold water and brine, dried, and solvents removed in vacuo. The residue was crystallized from ethyl acetate/hexanes to give 4-(1-benzenesulfonylpiperidin-4-ylmethyl)-phenylamine (0.29 g, 83%), m.p. 158° C.; Analysis for C18H22N2O2S: Calc.: C, 65.43; H, 6.71; N, 8.48; Found: C, 65.59; H, 6.61; N, 8.66.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[S:11][C:12]1[C:17]([C:18]([NH:20][CH2:21][C:22]23[CH2:31][CH:26]4[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]4)[CH2:23]2)[CH2:29]3)=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.B(Br)(Br)Br.CO>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[S:11][C:12]1[C:17]([C:18]([NH:20][CH2:21][C:22]23[CH2:31][CH:26]4[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]4)[CH2:23]2)[CH2:29]3)=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COc1ccc(OC)c(Sc2ncccc2C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccnc1Sc1cc(O)ccc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.7 %

Procedure:
To a solution of the dimethoxy compound from Example 37 (1.0 g) in dichloromethane (20 ml) at −78° C., was added boron tribromide (5.5 ml of a 1M solution in dichloromethane. The reaction mixture was stirred for 24 hours, warming to ambient temperature. Methanol (5 ml) was added and the solvent was removed under reduced pressure and the residue purified by silica gel chromatography eluting with dichloromethane, ethyl acetate, acetic acid (4:1:0.1). The fractions containing product were combined and the solvent removed under reduced pressure to give the title compound as a white solid (0.40 g).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:21][CH2:20]2)[CH:11]=1.O1CCCC1.N>O>[NH2:16][C:15]1[C:10]([Cl:9])=[CH:11][C:12]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:30])[C:26]([CH3:27])([CH3:28])[CH3:29])[CH2:21][CH2:20]2)=[N:13][CH:14]=1
Reactant: CC(C)(C)C(=O)N1CCN(c2cc(Cl)c([N+](=O)[O-])cn2)CC1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)N1CCN(c2cc(Cl)c(N)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add (4.5 mmol, 0.8 g) of sodium dithionite, over 1-[4-(4-chloro-5-nitro-pyridin-2-yl)-piperazin-1-yl]-2,2-dimethyl-propan-1-one (0.9 mmol, 0.3 g) in 22 mL of 1:1 mixture of tetrahydrofuran and water and 4 mL of ammonia. Stir the solution for 2 hours at room temperature. Concentrate under reduce pressure and extract the residue in ethyl acetate. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue that is used without further purification. MS(ES): m/z=297 [M+H].
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)cc4)CC3)nn2C(C)(C)C)cc1

Procedure:
82 mg (55%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(4-chlorophenyl)piperazine (80 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:11]=1[O:12][C:13]1[C:14]([CH2:30][C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[C:15]([O:28][CH3:29])[CH:16]=[CH:17][C:18]=1[C:19]2([CH3:27])[CH3:26])=O)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>O>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[NH2:8][CH2:9][C:10]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:11]=1[O:12][C:13]1[C:14]([CH2:30][C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:32])=[C:15]([O:28][CH3:29])[CH:16]=[CH:17][C:18]=1[C:19]2([CH3:27])[CH3:26]
Reactant: COc1ccc2c(c1CNC(=O)OC(C)(C)C)Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc2c(c1CN)Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C

Procedure:
2.9 g (5.29 mmol) of benzyl 5-[(1-tert-butoxyformamido)methyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate were taken up in a mixture of 10 ml of trifluoroacetic acid and 5 ml of water at 0°. After half an hour the solvents were removed, whereupon the residue was treated with 20 ml of ether. The resulting solid was filtered off, washed with ether and dried over magnesium sulphate, whereby 2.25 g of benzyl 5-aminomethyl-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate trifluoroacetate were obtained as a colourless powder of m.p. 169.5°-171°; IR 1716, 1662, 1631, 1604, 1538, 1494 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[S:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=1.O.[Cl-].[NH4+].ClCCl>C(O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:11]2[S:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[C:2]([F:1])[CH:7]=1
Reactant: O=C1CSC(c2ccc([N+](=O)[O-])cc2F)=NN1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: Nc1ccc(C2=NNC(=O)CS2)c(F)c1
Temperature: 90 °C
Yield: 91.6 %

Procedure:
2-(2-Fluoro-4-nitrophenyl)-4H-[1,3,4]thiadiazin-5-one (Step 4, 0.964 g, 0.00378 mol) is heated in ethanol (20 ml) until dissolved. Water (10 ml) and ammonium chloride (2.02 g, 0.0378 mol) are added and the mixture heated to 90° C. Iron powder (0.84 g, 0.0151 mol) is added portionwise and the mixture stirred and heated for 30 minutes. The reaction is cooled and dichloromethane (100 ml) added. The mixture is filtered and the organic layer separated, washed with saline, dried (MgSO4) and evaporated to give the title compound as a yellow solid (0.78 g, 92%), [M+H]+=226.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:61])[N:10]([C@@H:16]([CH2:36][CH2:37][CH:38]([F:60])[CH2:39][NH:40]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH2:1]([O:8][C:9](=[O:61])[N:10]([C@@H:16]([CH2:36][CH2:37][CH:38]([F:60])[CH2:39][NH2:40])[CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:33])[CH3:34])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCN(C(=O)OCc1ccccc1)[C@@H](CCC(F)CNC(c1ccccc1)(c1ccccc1)c1ccccc1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CC(C)CCN(C(=O)OCc1ccccc1)[C@@H](CCC(F)CN)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of the material from Step 9 (225 mg, 0.27 mmol) in dichloroethane (1.3 mL) at 0° C. was added trifluoroacetic acid (500 μL, 6.49 mmol). The reaction mixture was stirred at 0° C. for 1 hour, poured into saturated aqueous NaHCO3, and extracted with dichloromethane (2×). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using EtOAc-hexanes to afford 160 mg of the title compound. LCMS (M+1)=593.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=O.[NH2:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH:16]=2)[O:11][C:10]([CH3:30])([CH3:29])[CH:9]1[OH:31].[BH3-]C#N.[Na+].O>CO>[CH2:22]([NH:21][C:19](=[O:20])[CH2:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([CH3:29])([CH3:30])[CH:9]([OH:31])[CH:8]2[NH:7][CH2:1][C:2]([CH3:6])([CH3:5])[CH3:3])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)C=O
Reactant: CC1(C)Oc2ccc(CC(=O)NCc3ccccc3)cc2C(N)C1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)CNC1c2cc(CC(=O)NCc3ccccc3)ccc2OC(C)(C)C1O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
4 ml of trimethylacetaldehyde was added to a solution of 11 g of the 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-N-benzylacetamide obtained above in 200 ml methanol. 2.44 g of NaBH3CN was added in several portions, and the resulting suspension was stirred for 2 hours at 50° C. After cooling to room temperature, the reaction mixture was poured into 200 ml water. The aqueous phase was extracted once with 150 ml EA, the combined organic phases were dried over sodium sulfate, and the solvent was largely evaporated at reduced pressure. Chromatography of the remaining residue on silica gel (mobile phase: ethyl acetate/cyclohexane 1:1 v/v) and drying of the product fractions on a rotary evaporator yielded 10.8 g N-benzyl-2-[3-hydroxy-2,2-dimethyl-4-(neopentylamino)-3,4-dihydro-2H-chromen-6-yl]acetamide as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([C:6]#[N:7])=O.C(=O)(O)O.[NH2:17][NH:18][C:19]([NH2:21])=[NH:20].[N+]([O-])(O)=O.N>CS(C)=O>[NH2:20][C:19]1[N:18]=[N:17][C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[C:11]([Cl:12])[C:2]=2[Cl:1])=[C:6]([NH2:7])[N:21]=1
Reactant: N=C(N)NN
Reactant: N#CC(=O)c1cccc(Cl)c1Cl
Agent: N
Agent: O=C(O)O
Solvent: O=[N+]([O-])O
Solvent: CS(C)=O
Product: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1
Reaction time: 3 h
Yield: 16.6 %

Procedure:
A solution of 2,3-dichlorobenzoyl cyanide (32 g, 0.16M) in dimethylsulphoxide (80 ml) was added dropwise to a stirred suspension of aminoguanidine bicarbonate (81.67 g. 0.6M) which had been treated with 8N aqueous nitric acid (400 ml) at a temperature of ca 25° C. The mixture was stirred for 3 hours, then left to stand at room temperature for 7 days. The cooled mixture was stirred and basified with 0.880 aqueous ammonia (400 ml) at 20° C., then stirred with ice cooling for 30 minutes. The resulting solid was separated by filtration, washed thoroughly with water and finally dried in vacuo. The above solid was added to a 10% w/v solution of potassium hydroxide pellets in methanol (400 ml) and the solution heated to reflux for 11/2 hours. When cool the solution was evaporated down in vacuo, treated with ice water (800 ml) then stirred for 30 minutes and filtered. The residue was dried and recrystallised from isopropanol to give 3,5-diamino-(2,3-dichlorophenyl)-1,2,4-triazine Yield 6.8 g (15.6%), m.p. 216°-218° C. (uncorrected).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:9])=[O:4].[CH:13]([N:16]=[C:17]=[N:18][CH:19]([CH3:21])[CH3:20])([CH3:15])[CH3:14]>CCCCCC>[CH:19]([NH:18][C:17](=[N:16][CH:13]([CH3:15])[CH3:14])[O:9][CH2:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=1)([CH3:21])[CH3:20]
Reactant: CC(C)N=C=NC(C)C
Reactant: COC(=O)c1cccc(CO)c1
Solvent: CCCCCC
Product: COC(=O)c1cccc(COC(=NC(C)C)NC(C)C)c1
Yield: 95.7 %

Procedure:
A mixture of 4.75 g (28.6 mmols) of m-methoxycarbonylbenzyl alcohol and 3.6 g (28.6 mmols) of N,N'-diisopropylcarbodiimide was stirred with 50 mg (0.51 mmols) of cuprous chloride at room temperature for 24 hours. The reaction was then diluted with 10 ml of hexane and eluted through a short column of neutral alumina with 20% ethyl acetate-hexane to give 8.0 g (96%) of N,N'-diisopropyl-O-(m-methoxycarbonylbenzyl)-isourea as a colorless oil.
Reaction SMILES: IC.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4]1.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][O:13][C:12]([C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][NH:3]2)=[CH:7][CH:8]=1)=[O:14]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Iodomethane (0.75 mL, 12.0 mmol) was added to a suspension of indole-6-carboxylic acid (1.68 g, 10.5 mmol) and potassium carbonate (2.16 g, 15.7 mmol) in DMF (30 mL) under argon. The reaction was stirred at room temperature for 19 hr. The reaction was quenched with sat. NH4Cl and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0-60% EtOAc:Hexane). ESI-MS m/z 176 (MH)+.
Reaction SMILES: COC1N=CC([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH2:16]3)[CH2:11][CH2:10]2)=CC=1.O=C1CCN([C:44]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:45])CC1.COC1N=CC(N2CCC(=O)CC2)=CC=1>>[F:34][C:31]([F:32])([F:33])[C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH:23][CH2:22][C:21]([NH:20][C@@H:17]1[CH2:18][CH2:19][N:15]([CH:12]2[CH2:11][CH2:10][N:9]([C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[CH2:14][CH2:13]2)[CH2:16]1)=[O:36])=[O:35]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Agent: COc1ccc(N2CCC(=O)CC2)cn1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1

Procedure:
The title compound was synthesized in similar fashion to N-[2-({(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide, whereby benzyl 4-oxopiperidine-1-carboxylate was substituted for 1-(6-methoxypyridin-3-yl)piperidin-4-one, and was isolated as a white solid. 1H-NMR (CD3OD) δ: 1.30-1.45 (m, 2H), 1.64-1.18 (m, 1H), 1.84-2.00 (m, 2H), 2.08-2.38 (m, 2H), 2.50-2.64 (m, 2H), 2.80-3.00 (m, 4H), 3.20-3.40 (m, 2H), 4.03 (s, 2H), 4.08-4.13 (m, 2H), 4.34-4.44 (m, 1H), 5.12 (s, 2H), 7.35 (m, 5H), 7.70 (t, J=7.8 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.22 (s, 1H). MS m/z: 533 (M+1).
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[CH2:7]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[C:12]([F:18])[C:11]=1[F:19])[CH3:8]>O>[CH2:7]([O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:1])=[C:12]([F:18])[C:11]=1[F:19])[CH3:8]
Reactant: NOS(=O)(=O)O
Reactant: CCOc1ccc(C=O)c(F)c1F
Solvent: O
Product: CCOc1ccc(C#N)c(F)c1F
Temperature: 65 °C
Reaction time: 1 h

Procedure:
A mixture of 0.12 mole of hydroxylamine-0-sulfonic acid and 50 ml of water is added, at 30° C., to a mixture of 0.1 mole of 4-ethoxy-2,3-difluorobenzaldehyde and 100 ml of water, and the mixture is stirred for one hour. Warming to 65° C. for 2 hours and working up in the customary manner gives the nitrile in the form of a colourless solid, melting point 45° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C@@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[C@@H:18]1([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:17])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)C1(NC(=O)[C@H]2CCCc3ccccc32)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
The mixture of 2-[((S)-1,2,3,4-tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (69) (440 mg, 1.21 mmol) and KOH (800 mg, 14.2 mmol) is dissolved in EtOH (10 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 4 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more precipitate came out of the water. The precipitate is filtered to give a pure product (70) as white solid (405 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][C@@H:31]([C:35](O)=[O:36])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(N(CC)CC)C>O1CCOCC1>[NH2:8][C:7]1[C:2]([NH:1][C:35]([CH:31]2[CH2:32][CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:30]2)=[O:36])=[CH:3][CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)Nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2N)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (3.60 mmol) in 1,4-dioxane (20 mL) was added (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (3.60 mmol), 1-Propanephosphonic acid cyclic anhydride (10.8 mmol), and triethylamine (32.4 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and a solution of methanol/dichloromethane (1:9, 50 mL) was added followed by a saturated aqueous solution of sodium bicarbonate (50 mL), and the layers were separated. The aqueous layer was extracted again with methanol/dichloromethane (1:9, 25 mL) and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 3-((2-amino-6-((R)-3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)carbamoyl)piperidine-1-carboxylate which was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[N+:8]([O-:11])([O-])=[O:9].[Na+].[F:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[N:21]([CH3:23])[C:20](=[O:24])[CH2:19]2>>[F:13][C:14]1[CH:15]=[C:16]([N+:8]([O-:11])=[O:9])[CH:17]=[C:18]2[C:22]=1[N:21]([CH3:23])[C:20](=[O:24])[CH2:19]2
Reactant: CN1C(=O)Cc2cccc(F)c21
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)Cc2cc([N+](=O)[O-])cc(F)c21
Temperature: 25 °C

Procedure:
To a stirring suspension of trifluoroacetic acid (15 mL) and sodium nitrate (0.381 g, 4.48 mmol) was added 7-fluoro-1-methyl-1,3-dihydro-indol-2-one (7, 0.740 g, 4.48 mmol) and the reaction stirred at room temp. After 3½ hrs material poured onto ice water, filtered off resulting a precipitate. Dried on buchner funnel under vacuum overnight to give the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 3.4 (d, J=2.7 Hz, 3H) 3.6 (s, 2H) 8.0 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:13](=[O:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[C@@H:13]([OH:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)CCl
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
(3S)-3-Benzyloxycarbonylamino-1-chloro-5-methyl-2-hexanone (298.7 mg, 1.0 mmol) and a formic acid/triethylamine azeotropic mixture (0.2 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.67 mg, 0.001 mmol, s/c=1000) in ethyl acetate (1.0 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography to give a desired compound, (2R, 3S)-3-benzyloxycarbonylamino-1-chloro-2-hydroxy-5-methylhexane (295.6 mg; yield: 98.5%). HPLC analysis revealed that the production ratio of the desired (2R,3S)-form to the isomeric (2S,3S)-form, (2R,3S):(2S,3S), was 4.9:1. The results of elementary analysis were as follows.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[NH:54]1[C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=2[CH2:58][NH:57][CH2:56][C:55]1=[O:65]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11](=[O:13])[N:57]1[CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[NH:54][C:55](=[O:65])[CH2:56]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CNCc2ccccc2N1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CC(=O)Nc2ccccc2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.4 %

Procedure:
To a solution of (R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (90 mg, 0.26 mmol) in dry DCM (10 mL), was added HOBT (47 mg, 0.34 mmol), EDC (67 mg, 0.34 mmol) and DIPEA (0.24 mL, 1.35 mmol). The reaction mixture was stirred at r.t. for 10 min. A solution of 1,3,4,5-Tetrahydro-benzo[e][1,4]diazepin-2-one trifluoroacetate (74 mg, 0.26 mmol) in dry DCM (5 mL) was added and the reaction mixture was stirred at r.t. overnight under nitrogen atmosphere. After the completion of the reaction, as confirmed by TLC, the crude product was extracted with DCM (10 mL) and washed sequentially with 10% HCl solution (10 mL) and saturated sodium bicarbonate solution (10 mL). The organic layer was separated, washed with water, dried over Na2SO4 and concentrated in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 2:3 EtOAc:Pet.Ether) to afford [(R)-3-Oxo-3-(2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester (80 mg, 62%) as a white solid.