Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[OH:11][CH:12]([OH:16])[C:13](O)=O>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][O:10][CH:13]2[C:12]([OH:16])=[O:11]
Reactant: O=C(O)C(O)O
Reactant: Cc1ccccc1CCO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2c1CCOC2C(=O)O
Yield: 92.1 %

Procedure:
The mixture of 2-(2-methylphenyl)ethanol (2 g), TFA (10 ml) and 2,2-dihydroxyacetic acid (1.5 g) was refluxed for 23 hrs and volatiles were evaporated. Separation method I yielded the title compound (2.6 g) as an off-white solid. Alternatively, sulphuric acid can be used in cyclization.
Reaction SMILES: Br.[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[N:21]=2)=[CH:13]\[C@@H:14]2[NH:18][C:17](=[O:19])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].O>O1CCOCC1>[C:2]([C:6]1[CH:7]=[CH:8][C:9](/[C:12](/[C:20]2[NH:21][C:22](=[O:26])[CH:23]=[CH:24][CH:25]=2)=[CH:13]\[C@H:14]2[CH2:15][CH2:16][C:17](=[O:19])[NH:18]2)=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1cccc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)n1
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(/C(=C\[C@H]2CCC(=O)N2)c2cccc(=O)[nH]2)cc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
48% hydrobromic acid (0.5 mL) was added to a solution of the crude product of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one obtained in Example 4-185(2) (15 mg) in 1,4-dioxane (1 mL), and the mixture was stirred at 65° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→4:1). This was powdered with ethyl acetate-hexane to give the title compound as an orange powder (2 mg).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:33])[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:20]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:20]=[C:19]([CH3:33])[CH:24]=[CH:23][CH:22]=3)=[O:31])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(C)c3)n2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-m-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.75 min; [M+H]+=407.22.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH:24]([CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)[C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1CCOCC1.[NH2:54][CH2:55][C@@H:56]([NH:60][S:61]([C:64]1[CH:73]=[CH:72][C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=1)(=[O:63])=[O:62])[C:57]([OH:59])=[O:58]>C1COCC1.O>[C:43]([O:42][C:40]([N:37]1[CH2:36][CH2:35][CH:34]([CH2:33][CH2:32][CH:24]([CH2:23][CH2:22][CH:19]2[CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:21][CH2:20]2)[C:25]([NH:27][CH2:28][C:29]([NH:54][CH2:55][C@@H:56]([NH:60][S:61]([C:64]2[CH:73]=[CH:72][C:71]3[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=3)[CH:65]=2)(=[O:63])=[O:62])[C:57]([OH:59])=[O:58])=[O:30])=[O:26])[CH2:39][CH2:38]1)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: NC[C@@H](NS(=O)(=O)c1ccc2ccccc2c1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)NCC(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(CCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)NCC(=O)NC[C@@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)O)CC1
Reaction time: 0.33 h
Yield: 50.9 %

Procedure:
Isobutyl chloroformate (3.3 g, 24.2 mmol) is added, at room temperature, to a solution of 2-[(4-[1-(tert-butoxycarbonyl)-4-piperidyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidyl]ethyl}butanoyl)amino]acetic acid (compound 4) (10.8 g, 20 mmol) in 200 ml of THF and N-methylmorpholine (5 g, 49.5 mmol). A suspension is obtained. After stirring for 20 minutes, a mixture of (2R)-3-amino-2-[(2-naphthylsulphonyl)amino]propanoic acid (8 g, 25 mmol) and water (80 ml) is added, at 0° C. Stirring is continued at 0˜5° C. for 30 minutes and then at room temperature for 18 hours. The THF is evaporated off and the aqueous solution is acidified to pH 2 with 1N hydrochloric acid. The mixture is extracted with ether. The extracts are washed with water, dried over sodium sulphate and evaporated to give the crude product, which is purified by flash chromatography (10/0.5/0.5 dichloromethane/methanol/acetic acid) to give 8.3 g of a beige-coloured solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl>[O:11]([CH2:10][CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CNCCN1
Reactant: Clc1cncc(OCCOc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: c1ccc(OCCOc2cncc(N3CCNCC3)n2)cc1
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of the product from step 1 above (1.29 g, 5.15 mmol), piperazine (1.30 g, 15.1 mmol) and K2CO3 (0.71 g, 5.14 mmol) in acetonitrile (5 mL) was heated in a sealed pyrex flask at 100° C. for 4 h. The reaction mixture was diluted with dichloromethane, filtered, and concentrated in vacuo. The light-brown semi-solid residue was purified by silica gel chromatography (15×4 cm) using CHCl3/MeOH (9:1) as eluent. Solvents were evaporated off and the residue was redissolved in ether/CHCl3 (1:1). Filtration and concentration in vacuo furnished 1.05 g (68%) of the title compound as a white solid. HRMS m/z calcd for C16H20N4O2 (M)+ 300.1586, found 300.1578. Anal. (C16H20N4O2) C, H, N.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:6][CH2:5]2.CCCCCC.C([Li])CCC.[CH2:29]([O:31]CC)C.[Cl-].[NH4+]>O1CCCC1>[CH:29]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:6][CH2:5]2)=[O:31]
Reactant: CCOCC
Reactant: Brc1ccc2c(c1)CCC2OC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCC2OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8.1 g of 5-bromo-1-(tetrahydropyran-2-yloxy)indane was dissolved in 100 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere. To the solution was dropwise added 20 ml of a 1.5N n-butyllithiumhexan solution at -65° C. in 10 minutes. The resulting mixture was stirred at the same temperature for 5 minutes. Thereto was added 2.3 ml of anhydrous N,N-dimethylformaide. The reaction mixture was heated to room temperature and added to a mixture of 100 ml of ice water, 100 ml of diethyl ether and 2 g of ammonium chloride. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=15/1) to obtain 6.5 g of 5-formyl-1-(tetrahydropyran-2-yloxy)indane.
Reaction SMILES: [Cl-].[C:2]([CH2:5][N+]1C=CC=CC=1)(=[O:4])[NH2:3].[CH:12]([C:14](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])[C:15]#[N:16])=O.C(N(CC)CC)C.[Cl-].ClC=[N+](C)C>CO>[OH:4][C:2]1[CH:5]=[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:14]([C:15]#[N:16])=[CH:12][N:3]=1
Reactant: NC(=O)C[n+]1ccccc1
Reactant: Cc1ccccc1C=C(C#N)C=O
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccccc1-c1cc(O)ncc1C#N
Temperature: 45 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
1.726 g (10.0 mmol) 1-carbamoylmethyl-pyridinium chloride and 1.712 g (10.0 mmol) 2-formyl-3-o-tolyl-acrylonitrile in 24.8 ml methanol were treated with 1.05 g (10.4 mmol) triethylamine at 20-30° C. The reaction mixture was stirred for 2 hours and concentrated in vacuo (rotary evaporator at 40° C. and 20 mbar). The residue was taken up in 50 ml dichloromethane, treated with 2.56 g (20.0 mmol) (chloromethylene)dimethylammonium chloride (Vilsmeiers Reagent) and heated at 45° C. for 1 hour. In order to remove all volatile matter, the mixture was concentrated in vacuo (rotary evaporator at 45° C. and 20 mbar). The residue was heated to 180-190° C. for 15 minutes, cooled down to 20-25° C. and distributed in 80.0 ml dichloromethane and 80.0 ml water. The layers were separated. Evaporation of the organic phase in vacuo gave 1.37 g of amorphous product of 6-hydroxy-4-o-tolyl-nicotinonitrile.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[N:7]=[N:6]1.[NH:16]1[CH2:21][CH:20]=[C:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:18][CH2:17]1>>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:19]2[CH2:20][CH2:21][N:16]([CH2:2][CH2:3][CH2:4][N:5]3[C:10](=[O:11])[C:9]4[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=4[N:7]=[N:6]3)[CH2:17][CH:18]=2)=[CH:23]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: O=c1c2ccccc2nnn1CCCCl
Product: O=c1c2ccccc2nnn1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Yield: 78.8 %

Procedure:
Starting from 3-(3-chloropropyl)-1,2,3-benzotriazin-4(3H)one (1.49 g, 6.68 mmol) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)1-H-indole (1.32 g, 6.68 mmol), following the same procedure as in example 1, step 3; 2.03 g of 3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-1,2,3-benzotriazin-4(3H)-one was isolated as an off white solid. Yield 79%; mp 189° C.; MS: 386.2 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 2.20 (m, 2H), 2.57 (m, 2H), 2.66 (t, 2H), 2.72 (t, 2H), 3.21 (m, 2H), 4.61 (t, J=5.34 Hz, 2H), 6.15 (t, 1H), 7.12-7.21 (band, 2H), 7.26 (s, 1H), 7.35 (d, 1H), 7.75 (t, 1H), 7.87 (m, 2H), 8.13 (d, 1H), 8.36 (d, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@H:36]([NH:39][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and (S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].[CH:11]1([CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=O)=[CH:18][C:17]=2[F:25])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(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>[CH:11]1([CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]3[O:10][C:4]4[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=4[N:2]=3)=[CH:18][C:17]=2[F:25])[CH2:12][CH2:13]1
Reactant: Nc1ccc(O)cc1O
Reactant: O=C(O)c1ccc(OCC2CC2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
To a solution of 4-aminoresorcinol hydrochloride (5.00 g), 4-(cyclopropylmethoxy)-3-fluorobenzoic acid (5.91 g) and diisopropylethylamine (7.37 mL) in DMF (50 mL) was added HATU (11.8 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained solid was washed with ethyl acetate. To a solution of the obtained solid, hexachloroethane (16.7 g) and triphenylphosphine (18.5 g) in acetonitrile (50 mL) was added triethylamine (11.8 mL), and the mixture was stirred at room temperature for 15 min, and then with heating at 80° C. for 2 hr. The reaction mixture was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.23 g).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)(=O)C(Cl)=O.[CH:14]([C@H:17]1[CH2:21][O:20][C:19](=[O:22])[NH:18]1)([CH3:16])[CH3:15].[Li]CCCC>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[CH:14]([C@H:17]1[CH2:21][O:20][C:19](=[O:22])[N:18]1[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5])([CH3:16])[CH3:15]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: CCCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 52.1 %

Procedure:
To a stirred solution of pentanoic acid (5.98 g, 58.6 mmol) in CH2Cl2 (100 mL) and 10 drops DMF was added oxalyl chloride (5.64 mL, 64.4 mmol) dropwise over 5 min and the solution stirred for 2.75 h, at which time all bubbling subsided. The solution was concentrated in vacuo. In a separate flask, to a cold (−78° C.), stirred solution of (S)-4-isopropyloxazolidin-2-one (7.56 g, 58.6 mmol) in THF (280 mL) was added n-BuLi (2.5M in hexane, 23.42 mL, 58.6 mmol) dropwise via addition funnel over 20 min (temperature never exceeded −68° C.). After stirring 10 min, the above acid chloride dissolved in THF (50 mL) was added via addition funnel over 25 min. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. Water was added to the reaction mixture. The mixture was transferred to a separatory funnel and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to an amber oil. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 60% solvent A/B=hex/EtOAc, REDISEP® SiO2 120 g, applied as a DCM solution) to afford ((S)-4-isopropyl-3-pentanoyloxazolidin-2-one (6.51 g, 52%) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ ppm 4.44 (1H, ddd, J=8.16, 3.51, 3.39 Hz), 4.27 (1H, t, J=9.00 Hz), 4.21 (1H, dd, J=9.00, 3.01 Hz), 2.99 (1H, ddd, J=16.60, 8.50, 6.50 Hz), 2.86 (1H, ddd, J=16.60, 8.50, 6.78 Hz), 2.31-2.44 (1H, m), 1.56-1.72 (2H, m), 1.39 (2H, sxt, J=7.43 Hz), 0.94 (3H, t, J=7.28 Hz), 0.92 (3H, d, J=7.03 Hz), 0.88 (3H, d, J=6.78 Hz); HPLC: RT=2.497 min (CHROMOLITH® SpeedROD 4.6×50 mm (4 min grad) eluting with MeOH/H2O/0.1% TFA, 4 mL/min, monitoring at 220 nm); purity=100%.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH:32]=O)=[CH:24][CH:23]=1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:32][C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:22]=[CH:23][CH:24]=2)[CH2:11][CH2:10][N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C[C@H]1Cc1ccccc1
Reactant: O=Cc1ccnc2ccccc12
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5 g (17.2 mmol) of (2R*,4S*)-2-benzyl-1-t-butyloxycarbonyl-4-piperidinamine and 2.7 g (17.2 mmol) of quinoline-4-carboxaldehyde in 50 ml of toluene is stirred at room temperature and, after 2 hours, 2.8 g (23.3 mmol) of anhydrous magnesium sulfate are added. After a further 16 hours, the mixture is filtered and the filtrate is concentrated. The brown oil is dissolved in 50 ml of methanol, and 0.69 g (18.3 mmol) of sodium borohydride is added in 4 portions. After stirring at room temperature for 3 hours, the reaction mixture is concentrated, taken in ethyl acetate and washed with water and brine. The organic phases are dried over magnesium sulfate and evaporated to dryness. The brown oil is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia 850:50:1). The title compound is obtained as yellow oil. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.38, FD-MS: M+ =431.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]2([C:21]([O:23]CC)=[O:22])[O:15][N:14]=[C:13]([C:16]([O:18]CC)=[O:17])[CH2:12]2)=[CH:2]1.O.[OH-].[Li+]>C(O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]2([C:21]([OH:23])=[O:22])[O:15][N:14]=[C:13]([C:16]([OH:18])=[O:17])[CH2:12]2)=[CH:2]1
Reactant: CCOC(=O)C1=NOC(Cc2c[nH]c3ccccc23)(C(=O)OCC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1=NOC(Cc2c[nH]c3ccccc23)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.03 g (3.0 mmols) of diethyl 5-(RS)-(3-indolylmethyl)-4,5-dihydroisoxazole-3,5-dicarboxylate was dissolved in a mixed solvent of 16 ml of ethanol and 4 ml of water. 290 mg (6.9 mmols) of lithium hydroxide monohydrate was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to a volume of ⅓ or so under reduced pressure, and 15 ml of water and 1N hydrochloric acid were added to adjust the reaction solution to a pH of from 1 to 2. The resulting solution was extracted three times with 20 ml of ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The anhydrous magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 5-(RS)-(3-indolylmethyl)-4,5-dihydroisoxazole-3,5-dicarboxylic acid as a light yellow powder.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:6]1)#N.C([OH:24])C>>[OH:24][CH2:1][CH2:3][CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:6]1
Reactant: N#CCCC1C=C(c2ccccc2F)c2ccccc2C1
Reactant: CCO
Product: OCCCC1C=C(c2ccccc2F)c2ccccc2C1

Procedure:
A solution of 18 g of the preceding compound (XXXVII) in 200 ml of ~7 N hydrochloric ethanol and 200 ml of ethanol is brought to reflux for 36 hours. Then the solvent is evaporated, the residue is taken up in methylene chloride, washed with a sodium bicarbonate solution, then with water, dried on magnesium sulfate, filtered and the filtrate is evaporated. 15 g of the expected compound are obtained in the form of an oil.
Reaction SMILES: [CH2:1]([N:9]=[C:10]=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:12][NH:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1>>[CH2:1]([NH:9][C:10](=[O:11])[N:13]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN=C=O
Reactant: CCOC(=O)CCc1ccc(-c2cccc(NC)c2)cc1
Product: CCCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OCC)cc2)c1
Temperature: 100 °C
Yield: 101.3 %

Procedure:
464 μl (2.55 mmol, 1.5 eq) of octyl isocyanate are added to 482 mg (1.7 mmol, 1 eq) of ethyl 3-(3′-methylaminobiphenyl-4-yl)propanoate (prepared in Example 7c). The reaction mixture is heated at 100° C. by microwave for 30 minutes. The residue is chromatographed on silica gel (50 g FlashSmart Pack column) eluted with 70/30 heptane/ethyl acetate. 755 mg of ethyl 3-[3′-(3-octyl-1-methylureido)biphenyl-4-yl]propanoate are obtained in the form of a yellowish oil. Yield=100%
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:8]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)(=[O:20])=[O:19])[CH:7]2[CH2:29][C:30]([OH:32])=O)(=[O:3])[CH3:2].Cl.Cl.[NH:35]1[CH2:39][CH2:38][N:37]=[C:36]1[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][NH2:48])=[CH:42][CH:41]=1>>[ClH:27].[C:1]([C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:8]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)(=[O:19])=[O:20])[CH:7]2[CH2:29][C:30]([NH:48][CH2:47][CH2:46][C:43]1[CH:44]=[CH:45][C:40]([C:36]2[NH:37][CH2:38][CH2:39][N:35]=2)=[CH:41][CH:42]=1)=[O:32])(=[O:3])[CH3:2]
Reactant: NCCc1ccc(C2=NCCN2)cc1
Reactant: CC(=O)c1ccc2c(c1)C(CC(=O)O)N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1-2
Agent: Cl
Product: CC(=O)c1ccc2c(c1)C(CC(=O)NCCc1ccc(C3=NCCN3)cc1)N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1-2

Procedure:
The title compound was prepared from [8-acetyl-5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid and 2-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethylamine dihydrochloride (Reference Example 2) according to the method described in Example 1e. MS (EI) 662.3 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([C:14]([O:16]C)=[O:15])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnn(Cc2ccccc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)cnn1Cc1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 40.3 %

Procedure:
A mixture of methyl 1-benzyl-5-methyl-1H-pyrazole-4-carboxylate (200 mg, 0.86 mmol), lithium hydroxide monohydrate (111 mg, 2.62 mmol), tetrahydrofuran (10 mL), methanol (2 mL) and water (2 mL) was stirred at 20° C. for 4 hours. The mixture was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and separated by chiral HPLC (condition: column AD-H (20 mm*250 mm*5 μm), hexane:ethanol (0.2% DEA)=50:50, flow rate: 13 mL/min) to give 1-benzyl-5-methyl-1H-pyrazole-4-carboxylic acid (75 mg, 40%). LRMS (M+H+) m/z: calcd. 216.09. found 216.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][N:29]([CH3:34])[S:30](Cl)(=[O:32])=[O:31]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:30]([N:29]([CH3:34])[CH3:28])(=[O:32])=[O:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CN(C)S(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (28 mg, 26%), MS (ISP) m/z=438.3 [(M+H)+], mp 128° C., was prepared in accordance with the general method of example 26 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and dimethylsulfamoyl chloride.