Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[CH2:12]([O:19][C:20]([NH:22][C@H:23]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C1C=CC=CC=1.C(=O)C1C=CC=CC=1.[BH4-].[Na+]>O.C(OCC)(=O)C>[CH2:11]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]([C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30])[NH:22][C:20]([O:19][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:21])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: OCc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](CCCCNCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 2 h

Procedure:
Nα-Benzyloxycarbonyl-O-benzyl(L) lysine paratoluene sulphonate (5.5 g) in water (100 cm3) and ethyl acetate (200 cm3) was treated with sodium carbonate to pH 10. The ethyl acetate phase was washed with saturated brine (3×200 cm3), dried (anhydrous magnesium sulphate) and evaporated to an oil, yield=4.4 g of free amino compound. This was dissolved in chloroform (100 cm3), benzyl alcohol (10 cm3) and treated with 1.2 equivalents of benzaldehyde, stirred for 2 hours then treated with excess sodium borohydride. The solids were filtered off and the filtrate washed with saturated brine (5×150 cm3), dried and evaporated to an oil. This oil was dissolved in ether (300 cm3) and treated with para-toluene sulphonic acid in ether until in slight excess. An oil formed which crystallised at -10° overnight. The crystals were filtered off and washed with dry ether, then treated with sodium carbonate whilst stirring vigorously in ethyl acetate and water to pH 10. The organic phase was washed with saturated brine (4×100 cm3), dried and evaporated to afford the title compound as an oil, yield=3.1 g (57%) ν(film) 3330 (br), 1720, 750, 740, 700 cm-1, δ(CDCl3) 1.1-1.9 (6H, bm, NCH2 (CH2)3CH), 1.20 (1H, s, exchanges+D2O; CH2NH), 2.52 (2H, bt, J 6 Hz, NCH2 (CH2)3), 3.69 (2H, s, NCH2C6H5), 4.20-4.52 (1H, bm, ##STR11## 5.05 and 5.11 (2×2H, 2×s, 2×CO2CH2C6H5), 5.20-5.50 (1H, m, exchanges+D2O; NHCO2), 7.25 (5H, s) and 7.28 (10H, s); 3×CH2C6H5. C28H32N2O4 requires 460.2359; 460.2367 found m/e 460 (M+), 369 (M+--91), 308, 262, 261, 174, 160, 155, 120, 106, 92, 91 (100% I), 65. The title compound was obtained as a white crystalline solid from ethyl acetate-cyclohexane, ν (NUJOL) 3320 (broad), 1725, 1687, 1535, 750, 725, 695 cm-1. [α]D20 c=1% in chloroform=+0.61°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[OH2:25]>>[C:18](=[C:13]1[CH:14]=[N:15][CH:17]=[N:12]1)=[O:25].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O
Agent: Cl
Agent: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC[C@@H]1CN1CCCC1
Product: O=C=C1C=NC=N1

Procedure:
The compound was prepared by coupling of 1,1'-carbonyldimmidazole with 1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(1-pyrrolidinyl)methyl]piperazine; mp: (HCl salt) 148° C. (dec.); 1H NMR (free base, 200 MHz, CDCl3) δ1.5-1.7 (4 H, m), 2.1-2.5 (5 H, m), 2.6-3.4 (4 H, m), 3.5-4.8 (7 H, m), 6.9-7.4 (4 H, m), 8.0 (1 H, m); MS (FAB) 450 (M+H)+ ; Anal. Calcd for C21H25Cl2N5O2.2HCl. H2O: C, 46.60; H, 5.40; N, 12.94. Found: C, 45.41; H, 5.33; N, 12.73
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][C@H:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.Cl>ClCCl>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([O:19][CH2:18][C@@H:9]2[CH2:10][C@@H:11]([O:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OC(C)(C)C)cc1
Yield: 92 %

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (12.0 g) in dichloromethane (180 ml) stirring under ice cooling, triethylamine (6.23 ml), p-toluenesulfonyl chloride (8.52 g) and N,N-dimethylaminopyridine (993 mg) are successively added. The mixture is heated to reflux for 3 hours, supplemented with triethylamine (0.57 ml) and p-toluenesulfonyl chloride (775 mg), and heated to reflux for 1 hour. The reaction mixture is acidified with dilute hydrochloric acid. The organic layer is taken, washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography and recrystallized from n-hexane to give (2S,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol p-toluenesulfonate (16.8 g). Yield: 92%. mp. 65° to 66° C. NMR δ(CDCl3) ppm: 1.42(s, 9H), 2.15 to 2.55(m, 2H), 2.45(s, 3H), 3.03(s, 3H), 3.3 to 4.5(m, 5H), 5.1 to 5.25(m, 1H), 7.35(d, J=8.0 Hz, 2H), 7.76(d, J=8.0 Hz, 2H). IR ν (CHCl3) cm-1 : 1693.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OC([N:24]([C:32]1[S:41][CH2:40][C@H:39]2[C@@:34]([C:42]3[S:43][CH:44]=[C:45](Br)[CH:46]=3)([CH2:35][O:36][CH2:37][CH2:38]2)[N:33]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>CN(C=O)C.O.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:7]([C:45]2[CH:46]=[C:42]([C@@:34]34[N:33]=[C:32]([NH2:24])[S:41][CH2:40][C@@H:39]3[CH2:38][CH2:37][O:36][CH2:35]4)[S:43][CH:44]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(c3cc(Br)cs3)COCC[C@H]2CS1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(c3cc(-c4cccnc4F)cs3)COCC[C@H]2CS1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
2-Fluoropyridine-3-boronic acid (26.9 mg), tetrakis(triphenylphosphine)palladium (11.0 mg) and a 1 N sodium carbonate solution (191 μl) were sequentially added to a solution of (±)-N,N-di-(tert-butyloxycarbonyl)-[(4aR*,8aS*)-8a-(4-bromothiophen-2-yl)-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]amine obtained in Preparation Example 19-(3) (51.0 mg) in DMF (2.0 ml). After replacement with nitrogen, the mixture was stirred at 80° C. for five hours. The reaction solution was returned to room temperature and diluted with water. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain an intermediate. The resulting intermediate was dissolved in dichloromethane (5.0 ml). TFA (2.0 ml) was added and the mixture was stirred at room temperature for three hours. Ice was added to the mixture, followed by neutralization with a sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography to obtain the title compound (22.0 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([Si](CC)(CC)CC)=[C:7]2[CH2:20][CH2:21][NH:22][C:23](=[O:38])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)=[CH:26][CH:25]=1)(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:20][CH2:21][NH:22][C:23](=[O:38])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)=[CH:26][CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C(C)=O)cc2c1CCNC(=O)c1ccc(Cc2cccc(F)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc2[nH]cc(CCNC(=O)c3ccc(Cc4cccc(F)c4)cc3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.3 %

Procedure:
N-(2-(5-Acetyl-2-(triethylsilyl)-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide (0.043 g; 0.109 mmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at room temperature for 3 hours. The solution was concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) to afford 0.020 g (58%) of the title compound as a yellow foam.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][O:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:3]1.[CH3:40]I>CN(C=O)C>[CH3:40][O:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][O:20][C:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:3]1
Reactant: O=C(N[C@H]1CC[C@@H](O)C[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Reactant: CI
Solvent: CN(C)C=O
Product: CO[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
A sample of benzyl (1S,2R,4R)-4-hydroxy-2-(trityloxymethyl)cyclohexylcarbamate (6.9 g, 13.24 mMol) was dissolved in a mixture of MeI (12.4 mL, 198.6 mMol) and anhydrous DMF (15 mL) prior to the addition of Ag2O (6.1 g, 26.48 mMol) in one portion under an argon flush. The reaction was set to stir at rt in the dark. After stirring for 30 hr (the reaction was incomplete), it was diluted with CH2Cl2 and filtered through Celite. Filtered and concentrated to a yellow oil and flash chromatographed to get benzyl (1S,2R,4R)-4-methoxy-2-(trityloxymethyl)cyclohexylcarbamate (3.48 g) as a white foamy solid and recover the starting material.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2.[NH2:20][CH2:21][CH2:22][CH2:23][OH:24]>ClCCl>[O:24]([CH2:23][CH2:22][CH2:21][NH2:20])[Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NCCCO
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](C)(C)OCCCN
Temperature: 25 °C
Reaction time: 6 h

Procedure:
tert-Butyldimethylsilyl chloride (14.7 g, 97.5 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (14.6 ml, 97.5 mmol) was added to a solution 3-amino-1-propanol (7.45 ml, 97.5 mmol) in dichloromethane (100 ml) at 0° C. under argon. After 6 hours stirring at room temperature, the mixture was quenched with water and washed successively with 10% hydrochloric acid, saturated sodium bicarbonate solution and brine. Evaporation of the dried (magnesium sulfate) organic phase gave the title amine. 1 (HNMR(CDCl3): -0.03 (s, 6H), 0.81 (s, 9H), 1.61 (p, 2H, J=6.1 Hz), 2.20 (br, 2H), 2.75 (t, 2H, J=6.8 Hz) and 3.63 (t, 2H, J=6.12 Hz).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]([O:15]CC)=[O:14].O1CCCC1.O.[OH-].[Li+].Cl>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)/C=C/c1ccc2ccccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C/c1ccc2ccccc2c1
Reaction time: 18 h
Yield: 98.2 %

Procedure:
Combine ethyl trans-3-(naphth-2-yl)-propenoate (4.24 g, 18.8 mmol) and tetrahydrofuran (75 mL). Add lithium hydroxide hydrate (2.36 g, 56.3 mmol) in water (19 mL). After 18 hours, acidified to a pH of about 2 with aqueous 12 M hydrochloric acid solution to give a precipitate. Extract with ethyl acetate (3×150 mL). Dry the combined extracts over MgSO4, filter, and concentrated in vacuo to give trans-3-(naphth-2-yl)-propenoic acid as a white solid (3.66 g, 98% yield). NMR (CDCl3) δ 7.97 (d, 1H, J=15.7 Hz); 7.90 (d, 1H, J=15.3 Hz); 7.90-7.83 (c, 3H); 7.70 (dd, 1H, J=1.6, 8.6 Hz); 7.57-7.50 (c, 2H); 6.58 (d, 1H, J=16.0 Hz).
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[NH2:7][C:8]1[C:9]([CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)O)=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2>N1C=CC=CC=1>[CH3:1][N:2]1[S:3](=[O:5])(=[O:4])[NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[CH:11]=[CH:10][C:9]=2[CH:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1c(C(O)c2ccccc2)ccc2cccnc12
Reactant: CNS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN1C(c2ccccc2)c2ccc3cccnc3c2NS1(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.7 %

Procedure:
N-Methylsulfamoyl chloride (414 mg, 3.2 mmol) was added to a suspension of (8-amino-quinolin-7-yl)-phenyl-methanol (Intermediate 215) (200 mg, 0.8 mmol) in pyridine (5 ml) and the reaction was stirred at room temperature for 16 h. The solution was concentrated in vacuo. The crude residue was purified by column chromatography, with heptane/EtOAc (90:10-50:50) gradient elution to give the title compound (20 mg, 8%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2].C(O)C.O.[C:20]1([C@H:26]([OH:31])[C@@H:27]([NH2:30])[CH2:28][OH:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[C:20]1([C@H:26]([OH:31])[C@@H:27]([NH2:30])[CH2:28][OH:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2CC1C(=O)O
Agent: N[C@@H](CO)[C@@H](O)c1ccccc1
Solvent: O
Solvent: CO
Solvent: CCO
Product: CC(=O)N1c2ccccc2C[C@H]1C(=O)O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
100 g N-acetyl-indoline-2-carboxylic acid (purity 96.5%) was dissolved in 835 ml of a mixture containing 90% ethanol (EtOH), 5% water and 5% methanol (MeOH), with heating to 60° C., and with mechanical stirring. 54.4 g/0.69 eq. (1S,2S)-1-phenyl-2-amino-1,3-propanediol ([α]20D =+25.7° (c=1, MeOH)) was dosed in portions in 30 min. at 60° C. At the end spontaneous crystallization of the salt took place. After 30 minutes' subsequent stirring at 60-66° C., cooling to 15° C. took place, followed by another 30 minutes' stirring. After filtration over a P4 glass filter, three washings with 120 ml EtOH took place. After air-drying, 68.9 g off-white (S)-N-acetyl-indoline-2-carboxylic acid-(1S,2S)-1-phenyl-2-amino-1,3-propanediol salt was obtained, corresponding to a yield of 37.8%. Enantiomeric excess=96.3% (chiral HPLC).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[N:11]=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH:24]=[N:23][N:22]=[N:21]4)=[N:18][CH:19]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34].O>C(OCC)(=O)C>[N:20]1([C:17]2[N:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[CH:9]=[N:8][N:7]([CH:4]4[CH2:3][CH2:2][N:1]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:6][CH2:5]4)[N:11]=3)=[CH:15][CH:16]=2)[CH:24]=[N:23][N:22]=[N:21]1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Reactant: CC(C)OC(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1
Reaction time: 1 h

Procedure:
To a suspension of 5-((2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)methoxy)-2-(1H-tetrazol-1-yl)pyridine (Intermediate 15) (0.300 g, 0.917 mmol) in ethyl acetate (3 mL) was added triethylamine (0.169 mL, 1.22 mmol) and isopropyl chloroformate (1.10 mL, 1M solution in toluene, 1.10 mmol). The resulting solution was stirred for 1 hour. Water was added and the solution was extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel (1:1 hexanes/ethyl acetate) to obtain the expected product. 1H NMR (CDCl3): δ 9.45 (1H, s), 8.28 (1H, d), 8.03 (1H, d), 7.71 (1H, s), 7.58 (1H, dd), 5.28 (2H, s), 4.95 (1H, m), 4.64 (1H, m), 4.22 (1H, m), 2.21 (2H, m), 2.14 (2H, m), 1.26 (6H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12]C)[NH:8][C:7](=[O:14])[CH2:6][CH2:5]2.Br>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[NH:8][C:7](=[O:14])[CH2:6][CH2:5]2
Reactant: COc1cc2c(cc1Cl)CCC(=O)N2
Agent: Br
Product: O=C1CCc2cc(Cl)c(O)cc2N1
Yield: 89.2 %

Procedure:
The thus obtained 30 g of 6-chloro-7-methoxy-3,4-dihydrocarbostyril are dispersed in 300 ml of 47%-hydrobromic acid aqueous solution and heated for 4 hours under refluxing condition. After cooling of the reaction mixture, the insoluble matter is separated by filtration, washed with water and dried. Recrystallization from methanol-chloroform obtains 25 g of 6-chloro-7-hydroxy-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 264°-266° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1C(OCC)=O.Cl>[OH-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(C)c(OC)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(O)ccnc2c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A suspension of ethyl 4-hydroxy-7-methoxy-8-methylquinoline-3-carboxylate (58, 9.2 g, 35.2 mmol) in 5N NaOH (150 mL) was refluxed for 1.5 h (until a clear solution was obtained). Then, the solution was cooled to 0° C. and the pH adjusted to 2-3 with concentrated HCl. The solid was filtered off and successively washed with water, acetone and ether. This powder was added in small portions to diphenylether (40 mL), pre-heated at 250° C. The resulting suspension became a solution after 20 min (CO2 formation was observed). After 1 h at 250° C., the brown solution was cooled to room temperature and diluted with heptanes (200 mL). The precipitate was filtered off and washed with heptanes and ether to give 6.4 g (96%) of the target product 59 as a yellow powder: m/z=190 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1N.S(=O)(=O)(O)O.C(O)(C)C.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1cc(Cl)cc(Cl)c1
Yield: 90 %

Procedure:
206 parts of 3,5-dichloroanthranilic acid are introduced into 500 parts of 45 percent strength by weight sulfuric acid and 400 parts of isopropanol. A solution of 100 parts of sodium nitrite in 140 parts of water is run in over 5 hours at 80° C.; nitrogen is evolved. The mixture is cooled, 1,000 parts of water are added and the product is filtered off. 172 parts (90% of theory) of 3,5-dichlorobenzoic acid of melting point 175°-178° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH2:13]>[Pd].CCO>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cccc(N)c1N
Reaction time: 1 h

Procedure:
2-Amino-3-nitro benzoic acid methyl ester 1 (1.0 g, 5.1 mmol) and palladium on carbon (10%, 0.5 g) were mixed in EtOH (20 mL) and were hydrogenated at 15 psi for 1 h. The catalyst was filtered off and the filtrate was concentrated in vacuo. The resulting solid was dried to give 0.73 g (86%) of pure 2: 1H NMR (CDCl3) δ 7.47 (d, 1H, J=8.0 Hz), 6.85 (d, 1H, J=6.5 Hz), 6.60 (t, 1H, J=8.0 Hz), 3.87 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+].[CH3:27][C:28]1C=C(C2(C3C=C(Br)C(O)=C(C)C=3)OS(=O)(=O)C3C2=CC=CC=3)C=C(Br)C=1O.C(=O)C>CO.O.CO.Cl>[CH2:27]([N:20]1[CH2:21][CH2:22][CH:17]([CH:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:10])[CH2:12][CH2:13]2)[CH2:18][CH2:19]1)[CH3:28]
Reactant: Cc1cc(C2(c3cc(C)c(O)c(Br)c3)OS(=O)(=O)c3ccccc32)cc(Br)c1O
Reactant: O=C(OCc1ccccc1)N1CCC(C2CCNCC2)CC1
Agent: CC=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: O
Solvent: CO
Product: CCN1CCC(C2CCN(C(=O)OCc3ccccc3)CC2)CC1

Procedure:
To a solution of 18.14 g (0.061 mol) of 1-(phenylmethoxycarbonyl)-4-(4-piperidinyl)piperidine in 450 ml of a methanol/water mixture (1/1 v/v) were added, with stirring, whilst maintaining a temperature of 15 to 20° C., 10.05 g (0.152 mol) of 95% sodium cyanoborohydride and 50 mg of bromocresol purple. Then a solution of 10.57 g (0.24 mol) of acetaldehyde in 50 ml of methanol and 1N hydrochloric acid were alternately added dropwise so that the colour of the mixture changed continuously from blue to yellow. After all had been added and the reaction had finished the mixture was adjusted to pH 2 with hydrochloric acid and extracted twice with 200 ml of diethylether. The aqueous phase was then made alkaline and extracted thoroughly with dichloromethane. The combined dichloromethane extracts were dried over magnesium sulphate and evaporated down in vacuo. The colourless crystallising residue remaining was purified by column chromatography over silica gel (30-60 μm) using FM1 as eluant. Yield of colourless crystals of melting point 93-96° C.: 7.9 g (39.26 of theory).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][CH:6]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:7]([NH:9][NH2:10])=O.Cl.Cl.[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[CH:33]=[CH:34]/[C:35](=[NH:39])OCC)[CH:24]=[CH:25][C:26]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1.C(OCC)(=O)C.O>C(O)C>[CH:11]1([CH:6]2[CH2:5][CH2:4][CH2:3][N:9]3[N:10]=[C:35](/[CH:34]=[CH:33]/[C:23]4[CH:24]=[CH:25][C:26]([N:27]5[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]5)=[C:21]([O:20][CH3:19])[CH:22]=4)[N:39]=[C:7]23)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Reactant: NNC(=O)C(CCCCl)C1CCCCC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCCCC2)ccc1-n1cnc(C)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 13.9 %

Procedure:
A solution of 5-chloro-2-cyclohexyl-valeric acid hydrazide hydrochloride (144 mg) and TEA (0.32 ml) in ethanol (1 ml) was added to a solution of ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride obtained in Example 1 (167 mg) and TEA (0.32 ml) in ethanol (1.6 ml), and the reaction solution was stirred at 70° C. for two days. The reaction solution was left to cool to room temperature. Then, ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetate system) and again purified by silica gel column chromatography (elution solvent: ethyl acetate-methanol system) to obtain 27 mg of racemic 8-cyclohexyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine. Then, the racemate was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: 20% ethanol-hexane) to obtain the title optically active compound with a retention time of 16 minutes and positive optical rotation (11.0 mg; 100% ee) and the title optically active compound with a retention time of 39 minutes and negative optical rotation (10.2 mg; 100% ee).