Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:12]=2)[NH:8][N:9]=1)=O.[BH4-].[Li+].Cl.C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:12]=2)[NH:8][N:9]=1
Reactant: COC(=O)c1cc(Nc2nc(-c3ccccc3)nc3ccccc23)[nH]n1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cc(Nc2nc(-c3ccccc3)nc3ccccc23)[nH]n1
Temperature: 25 °C

Procedure:
A solution of (5-Methoxycarbonyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine (III-73) (345 mg, 1 mmol) in anhydrous THF (10 mL) was treated with lithium borohydride (125 mg, 5.75 mmol) at 65° C. for 5 hours. The mixture was cooled to room temperature then combined with 2M HCl and ethyl acetate. Solid sodium hydrogen carbonate was added to achieve pH 8 and the resulting mixture extracted with ethyl acetate. The extracts were dried over magnesium sulphate and concentrated. Purification by flash chromatography (SiO2, methanol-dichloromethane gradient) afforded III-74 (95 mg, 30%) as an off-white solid: mp 238–239° C.; 1H NMR (DMSO) δ 4.58 (2H, d, CH2), 5.35 (1H, s, OH), 6.94 (1H, s), 7.50–7.60 (4H, m), 7.85–7.90 (2H, m), 8.48–8.54 (2H, m), 8.69 (1H, 1H), 10.40 (1H, s), 12.48 (1H, s); IR (solid) 1652, 1621, 1603, 1575, 1558, 1539, 1532, 1480, 1373, 1320, 1276, 1175, 1057, 1037, 1007, 951, 865, 843, 793, 780, 7124; MS 318.2(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[N:32]1([CH2:38][C:39]([NH:41][CH:42]([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([N:35]3[CH2:34][CH2:33][N:32]([CH2:38][C:39]([NH:41][CH:42]([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:36]3)=[O:23])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: CC(C)NC(=O)CN1CCNCC1
Product: CC(C)NC(=O)CN1CCN(C(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-piperazinyl-N-isopropylacetamide as in General Procedure 10 to give the title compound. LCMS: m/z=615.01 (M+H+); retention time=0.61 minutes.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].[H-].[Na+].[CH2:14](I)[CH3:15]>CN1CCCC1=O>[CH2:1]([N:4]([CH2:14][CH3:15])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCNC(=O)OC(C)(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C=CCN(CC)C(=O)OC(C)(C)C

Procedure:
The sub-titled compound was prepared from tert-butyl allylcarbamate (1.0 g), 60% sodium hydride (0.254 g), ethyl iodide (1.55 ml) and anhydrous N-methyl-2-pyrrolidinone (4 ml) by the method of Example 2(ii). The crude product was purified by chromatography on silica gel eluting with iso-hexane:ethyl acetate (19:1) to afford (0.53 g) of a colourless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[C:10]3[O:11][CH:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:13][CH2:14][C:15]=3[C:16]([C:18](O)=[O:19])=[CH:17][C:8]=2[N:7]=[C:6]1[CH3:27].[CH2:28]([N:30](CC)[CH2:31]C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.CNC>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[C:10]3[O:11][CH:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:13][CH2:14][C:15]=3[C:16]([C:18]([N:30]([CH3:31])[CH3:28])=[O:19])=[CH:17][C:8]=2[N:7]=[C:6]1[CH3:27]
Reactant: CCN(CC)CC
Reactant: COCCn1c(C)nc2cc(C(=O)O)c3c(c21)OC(c1ccccc1)CC3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Product: COCCn1c(C)nc2cc(C(=O)N(C)C)c3c(c21)OC(c1ccccc1)CC3
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(2-methoxyethyl)-2-methyl-8-phenyl-1,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxylic acid (200 mg, 0.55 mmol, Step 12), triethylamine (0.30 mL, 2.18 mmol), and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (228 mg, 0.60 mmol) in N,N-dimethylformamide (5 mL) was added dimethylamine hydrochloride (49 mg, 0.60 mmol) at 0° C. After stirring at room temperature for 12 h, the mixture was poured onto water, and the aqueous layer was extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (20:1) to afford the title compound as a white amorphous (215 mg, quant.).
Reaction SMILES: C([C:4]1([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[CH2:5]1)(O)=O.O.C(OC(=O)C)C>CN1CCCC1=O>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:13])[CH2:5]2)=[CH:19][CH:18]=1
Reactant: O=C1CC(C(=O)O)(c2ccc(F)cc2)c2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CC(c2ccc(F)cc2)c2ccccc21
Reaction time: 2 h

Procedure:
The following operations are performed under dry nitrogen. A solution of 40.0 gr 3-carboxy-3-(4-fluorophenyl)-indan-1-one in 50 ml N-methylpyrrolidone is heated to 100° C. and stirred for 2 hours at this temperature. The reaction-mixture is cooled and poured into 250 ml water. Subsequent extractive work-up with ethylacetate give the product 3-(4-fluorophenyl)-indan-1-one.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([CH3:22])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH3:14])=[C:9]([CH:12]=1)[CH:10]=[O:11].CC(=CC)C.Cl([O-])=[O:29].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>O1CCCC1.C(O)(C)(C)C.OP([O-])(O)=O.[K+]>[CH3:22][C:15]1[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=[C:2]([CH3:1])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH3:14])=[C:9]([CH:12]=1)[C:10]([OH:29])=[O:11]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.3 %

Procedure:
To a solution of 5-(2,6-dimethyl-4-nitro-phenoxy)-2-methoxy-benzaldehyde (6.6 g, 21.8 mmol) and 2-methyl-2-butene (23.0 g, 327 mmol) in a mixture of tetrahydrofuran (31 mL) and t-butyl alcohol (210 mL) at room temperature was added dropwise a solution of sodium chlorite (17.7 g, 196 mmol) in KH2PO4 (0.6 M, 254 mL). The resulting mixture was stirred at room temperature for 16 hours, and then saturated aqueous Na2S2O3 (100 mL) was added. The solution was stirred at room temperature for 30 minutes and extracted with ethyl acetate (3 times 300 mL). The combined organic extracts were dried over Na2SO4 and concentrated to afford the title compound (7.7 grams) as a crude product. The product was used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ8.01 (s, 2H), 7.49 (s, 1H), 7.02 (s, 2H), 4.06 (s, 3H), 2.19 (s, 6H). MS (APCI−) Calc: 317.3, Found: 316.3 (M−1).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([OH:30])=O)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:35]([O:37][C:38](=[O:41])[CH2:39][NH2:40])[CH3:36].C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([NH:40][CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:41])=[O:30])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a mixture of (±)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid (150 mg, 0.345 mmol), glycine ethyl ester hydrochloride (63 mg, 0.449 mmol) and diisopropylethylamine (0.078 ml, 0.449 mmol) in DMF (5 ml) was added 1-hydroxybenzotriazole (70 mg, 0.518 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (132 mg, 0.690 mmol). After stirring the resulting mixture at room temperature for 3 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with 1N-hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water and brine successively, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 2:1 elution) to give ethyl (±)-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-benzoylamino}acetate (168.9 mg, 94%).
Reaction SMILES: Cl.[NH2:2][OH:3].O=[C:5]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]>CO>[OH:3][N:2]=[C:5]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: NO
Reactant: COC(=O)C(=O)c1ccc(C(C)C)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)C(=NO)c1ccc(C(C)C)cc1
Reaction time: 8 h

Procedure:
Hydroxylamine hydrochloride (0.87 g) was added to a stirred solution of the previously obtained mixture of methyl 2-oxo-2-(4-isopropyl-phenyl)acetate and methyl 4-isopropylphenyl acetate (1.29 g) in methanol (20 ml). When the solid had dissolved the mixture was left overnight. The solvent was evaporated and the residue partitioned between ethyl acetate and water, the organic phase was washed with water and brine, dried over magnesium sulphate and evaporated. The product (307 mg) was obtained by column chromatography of the residue using gradient elution (Kieselgel 3:1 to 1:1 hexane:ethyl acetate). νmax (CHCl3)/cm-1 3568, 3295 and 1738. δH (250 MHz, CDCl3), 1.28 (6H, d, J 6.87), 2.95 (1H, heptet, J 6.92), 3.88 (3H, s), 7.32 (2H, dd, J 1.81 and 6.47), 7.47 (2H, dd, J 1.83 and 6.65), 9.59 (1H, s).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][NH:21][C:22](=[O:34])[NH:23][C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([O:29]C)=[O:28])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].C(O)(=O)C>CO.O1CCCC1.O>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][NH:21][C:22](=[O:34])[NH:23][C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([OH:29])=[O:28])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cccc(NC(=O)NCc2nc3ccccn3c2C#Cc2cccc(C(F)(F)F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C(NCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1)Nc1cccc(C(=O)O)c1
Yield: 69.7 %

Procedure:
0.038 g (0.078 mmol) of methyl 3-(3-((3-((3-(trifluoromethyl)phenyl)ethynyl) imidazo[1,2-a]pyridin-2-yl)methyl)ureido)benzoate were dissolved in 2 ml of a methanol/tetrahydrofurane mixture (1/1, v/v) with magnetic stirring and then 0.931 ml (0.931 mmol) of a (1M) NaOH aqueous solution were added and the mixture was stirred at r.t. for 16 h before being treated with a solution of 0.053 ml (0.931 mmol) of acetic acid in 10 ml of water. The mixture was stirred at r.t. for 30 min. The solid formed was isolated by filtration, washed with 5 ml of water and dried in a vacuum bell jar in order to obtain 0.026 g (yield=70%) of 3-(3-((3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methyl) ureido) benzoic acid as a white solid. LC-MS: m/z=479 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 12.83 (s, 1H), 8.96 (s, 1H), 8.73 (d, J=6.7 Hz, 1H), 8.04 (s, 2H), 7.90 (d, J=7.5 Hz, 1H), 7.69 (dd, J=13.0, 8.4 Hz, 2H), 7.58 (d, J=7.7 Hz, 2H), 7.45 (d, J=7.5 Hz, 2H), 7.29 (t, J=7.9 Hz, 1H), 7.13 (t, J=6.8 Hz, 1H), 6.80 (t, J=5.4 Hz, 1H), 4.62 (d, J=5.6 Hz, 2H).
Reaction SMILES: C(=O)=O.CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:14]([O:18][C:19](=[O:30])[N:20]([C@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24][CH2:23]1)[CH3:21])([CH3:17])([CH3:16])[CH3:15].CCN(CC)CC>C(Cl)Cl>[C:14]([O:18][C:19](=[O:30])[N:20]([CH:22]1[CH2:23][CH2:24][CH:25]([CH:28]=[O:29])[CH2:26][CH2:27]1)[CH3:21])([CH3:15])([CH3:17])[CH3:16]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CO)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN(C(=O)OC(C)(C)C)C1CCC(C=O)CC1
Reaction time: 0.08 h
Yield: 100.4 %

Procedure:
To a dry-ice cooled solution of 8.94 ml (125.9 mmol) DMSO in 150 ml CH2Cl2 was added 5.95 ml (69.24 mmol) oxalylchloride. After 5 min at −78° C., a solution of 16.2 g (66.5 mmol) trans-(4-Hydroxymethyl-cyclohexyl)-methyl-carbamic acid tert-butyl ester in 50 ml of CH2Cl2, was added slowly. 10 min later, 43.8 ml (314.75 mmol) of Et3N was added, and the mixture was allowed to attain RT. The mixture was partitioned between Et2O/1N HCl and water. The solvent was evaporated under reduced pressure yielding 16.12 g of clean (4-Formyl-cyclohexyl)-methyl-carbamic acid tert-butyl ester, MS: 241 (M).
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25](Br)[CH:26]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N#N>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:4]([O:3][C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[CH:24]=[N:23][CH:22]=[C:21]([Cl:20])[CH:26]=1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: Clc1cncc(Br)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: N#N
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1c(-c2cncc(Cl)c2)cc2ccccc21
Temperature: 25 °C

Procedure:
A flask is charged with N-Boc-indole-2-boronic acid (0.407 g, 1.55 mmol), 3-chloro-5-bromopyridine (0.200 g, 1.03 mmol), s-phos (0.021 g, 0.05 mmol), potassium phosphate (0.441 g, 2.07 mmol) and toluene (5 mL). The flask is evacuated and filled with N2 thrice and Pd2(dba)3 (0.019 g, 0.02 mmol) is added. The flask is evacuated and filled with N2 thrice. The mixture is refluxed for 1 h, then cooled to room temperature and filtered through celite. The filtrate is concentrated in vacuo to afford 2-(5-chloro-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester as an oil. The residue is dissolved in DCM (5 mL) and trifluoroacetic acid (2 mL) is added. The reaction mixture is stirred at room temperature for 4 h, followed with quenching with a saturated sodium bicarbonate solution. Extraction with dichloromethane, drying of the organic layer over sodium sulfate and concentration in vacuo gives a residue which is purified by silica gel flash chromatography (heptane-ethyl acetate, 3:2) to afford 2-(5-chloro-pyridin-3-yl)-1H-indole. 1H NMR (400 MHz, MeOD) δ ppm 7.06 (s, 1H), 7.08 (d, J=7.8 Hz, 1H), 7.20 (t, J=7.7 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 8.30 (t, J=2.1 Hz, 1H), 8.47 (d, J=2.3 Hz, 1H), 8.96 (d, J=1.8 Hz, 2H). HRMS (ESI) m/z 229.0542 [(M+H)+ calcd for C13H10ClN2: 229.0533].
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[OH:4].CCN(CC)CC.C(Cl)Cl.[Cl:29][CH2:30][C:31](Cl)=[O:32]>CO>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH2:2][NH:1][C:31](=[O:32])[CH2:30][Cl:29])=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)CCl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)NCC(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To a mixture of 2-amino-1-(4-benzyloxy-phenyl)-ethanol (20.10 g; 82.6 mmol), Et3N (13.82 mL; 99.1 mmol), CH2Cl2 (200 mL) and MeOH (20 mL) was added dropwise chloroacetyl chloride (7.24 mL; 90.9 mmol) at −10° C. The resulting mixture was allowed to warm to RT and stirred overnight, and subsequently concentrated in vacuo. The residue was purified by flash chromatography (SiO2, EtOAc) to afford N-[2-(4-benzyloxy-phenyl)-2-hydroxy-ethyl]-2-chloro-acetamide (17.45 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[N:10]([CH2:19][CH:20]=O)[C:9](=[O:22])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][N:34]([CH:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO.C(O)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[N:10]([CH2:19][CH2:20][N:45]3[CH2:46][CH2:47][CH:42]([N:34]([CH2:33][C:31]4[CH:30]=[CH:29][C:28]5[O:23][CH2:24][CH2:25][O:26][C:27]=5[CH:32]=4)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:38])[CH3:39])[CH2:43][CH2:44]3)[C:9](=[O:22])[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: COc1ccc2c(C(=O)NC3CC3)cc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2c(C(=O)NC3CC3)cc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
To 1.0 mL of methanol solution containing 0.13 g of N-cyclopropyl-7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxamide, 0.16 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 25 μL of acetic acid were added at room temperature and stirred at the same temperature for 1.5 hours. To the reaction mixture, 42 mg of sodium cyanoborohydride was added and stirred at the same temperature for 2 hours. Further, 42 mg of sodium cyanoborohydride was added and stirred at the same temperature for 2 hours and 15 min. 76 μL of acetic acid was added and stirred at the same temperature for 2 hours. To the mixture, aqueous saturated sodium hydrogen carbonate solution was added under ice-cooling to be adjusted to pH 8.7, 5.0 mL of methanol and 15 mL of chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash silica gel column chromatography [gradient elution of chloroform:methanol=100:0-70:30], to give 0.13 g of tert-butyl (1-(2-(4-((cyclopropylamino)carbonyl)-7-methoxy-2-oxoquinolin-1-(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate as a white foam.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:13]=[CH:12]O[C:10](=[O:14])[C:9]=2[CH:15]=1)[CH2:2][CH2:3][CH3:4].[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[N:34]([CH2:35][O:36][CH3:37])[N:33]=[N:32][N:31]=2)=[CH:20][CH:19]=1.O>C1(C)C(C)=CC=CC=1>[CH2:1]([C:5]1[CH:15]=[C:9]2[C:8](=[CH:7][CH:6]=1)[N:13]=[CH:12][N:16]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([CH2:35][O:36][CH3:37])[N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=1)[C:10]2=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc2ncoc(=O)c2c1
Reactant: COCn1nnnc1-c1ccccc1-c1ccc(CN)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCc1ccc2ncn(Cc3ccc(-c4ccccc4-c4nnnn4COC)cc3)c(=O)c2c1
Yield: 43.5 %

Procedure:
A mixture of 6-n-butyl-4H-3,1-benzoxazin-4-one (1.4 g, 6.89 mmol) and 5-(4'-aminomethylbiphenyl-2-yl)-N-methoxymethyltetrazole (2.85 g, ca. 9.65 mmol) in xylene (50 ml) was heated under reflux for 8 hours while water was removed by a Dean-Stark trap. After cooling, the reaction mixture was concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel. The column was eluted with chloroform-ethyl acetate (1% to 10%) to give 1.44 g (43.6%) of the title compound as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:23][C:24]([OH:26])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].CN(C)C=O.C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:23][C:24]([Cl:35])=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 69 h

Procedure:
To a mixture of 10 g of product from Example 64, 0.095 g of dimethylformamide and 150 ml of methylene chloride is added, dropwise, 3.42 ml of oxalyl chloride. The reaction is stirred at room temperature for 69 hours and then concentrated in vacuo. The residue is dissolved in diethyl ether, filtered and concentrated in vacuo to give 10.5 g of the desired product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([N:13]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:30][CH:29]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21]C1CCCCO1)(=[O:12])=[O:11].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[OH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][N:13]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:30][CH:29]=1)[S:10]([C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])(=[O:12])=[O:11]
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2ccccc2OC2CCCCO2)c2ccc(OCCN3CCCC3)cc2)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccccc2O)c2ccc(OCCN3CCCC3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.6 %

Procedure:
To a solution of 2,4,6-trimethyl-N-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-N-[2-(tetrahydro-pyran-2-yloxy)-benzyl]-benzenesulfonamide (0.039 g, 0.07 mmol) in 4 mL absolute ethanol was added 1 mL of 1.2N HCl. The reaction mixture was stirred at room temperature for 24 hr. and was poured into saturated aqueous sodium bicarbonate. The aqueous solution was washed with two portions of ethyl acetate. The combined organic layers were dried (sodium sulfate), filtered, and concentrated. The residue was purified by preparative TLC (1.0 mm silica gel layer, eluting with 10% methanol/methylene chloride) to afford 0.004 g of the title compound. MS 494.8 (M+1)+