Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@@H]([C@@H]1[C@@:12]2(C)[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@]4(C)C[CH2:22][C@@H:23](O)[CH2:24][C@H:19]4[CH2:18][CH2:17][C@@:16]3(C)[C@@H:11]2[CH2:10][CH2:9]1)CCC([O-])=O.[Na+].[OH:31][CH2:32]C(CO)O>>[CH3:12][C:13]([CH2:14][CH2:15][C:16]1[CH:11]=[CH:10][C:9]2[CH:22]=[C:23]([O:31][CH3:32])[CH:24]=[CH:19][C:18]=2[CH:17]=1)=[O:28]
Reactant: OCC(O)CO
Reactant: C[C@H](CCC(=O)[O-])[C@H]1CC[C@H]2[C@]3(C)CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: [Na+]
Product: COc1ccc2cc(CCC(C)=O)ccc2c1

Procedure:
A weighed quantity of the drug material and a volume of a solution containing 2.2% Poloxamer 188, 0.1% sodium deoxycholate, and 2.2% glycerin adjusted to pH 8.7 were combined and mixed under high shear to form a pre-suspension. The pre-suspension was homogenized for 20 discrete passes at a pressure of 25,000 psi.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:20]([CH2:23][CH3:24])([O-:22])=[O:21]>C(OC(C)C)(C)C>[CH3:14][O:13][C:8]1[CH:7]=[C:4]([CH:5]=[C:23]([N+:20]([O-:22])=[O:21])[CH3:24])[C:3]([O:2][CH3:1])=[C:10]([CH3:11])[C:9]=1[CH3:12]
Reactant: CC[N+](=O)[O-]
Reactant: COc1cc(C=O)c(OC)c(C)c1C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(C)OC(C)C
Product: COc1cc(C=C(C)[N+](=O)[O-])c(OC)c(C)c1C
Yield: 67 %

Procedure:
A mixture of 2,5-dimethoxy-3,4-dimethylbenzaldehyde (38.9 g, 0.20 mol), ammonium acetate (10 g, 0.13 mol) and nitroethane (200 mL) was heated to reflux for 2 hours. The reaction mixture was diluted with diisopropyl ether, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 33.6 g of the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:34])[CH:11]=1>>[CH:31]1([C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([C:13]4[CH:14]=[CH:15][C:10]([N:4]5[CH2:3][C@@H:2]([CH3:1])[CH2:6][S:5]5(=[O:8])=[O:7])=[CH:11][C:12]=4[F:34])=[O:17])[CH2:23][CH2:22]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: C[C@@H]1CNS(=O)(=O)C1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C[C@@H](C)CS3(=O)=O)cc2F)CC1
Yield: 34.4 %

Procedure:
Using (R)-4-methylisothiazolidine 1,1-dioxide (180 mg) described in Preparation Example 7 and (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (371 mg) described in Preparation Example 121 and by the reaction and treatment in the same manner as in Example 4, the title compound (144 mg) was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[N:18][O:19][C:20]=3[CH3:21])=[O:15])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].O[Li].O>C1COCC1.O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:17]2[C:16]([C:14]([C:9]3[C:8]4[C:12](=[CH:13][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=4)[NH:11][CH:10]=3)=[O:15])=[C:20]([CH3:21])[O:19][N:18]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc2c(C(=O)c3c(-c4ccc(F)cc4)noc3C)c[nH]c2c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1c[nH]c2cc(C(=O)O)ccc12
Yield: 96.4 %

Procedure:
To a solution of 0.7 g (1.85 mmol) 3-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-1H-indole-6-carboxylic acid methyl ester in 12 mL of THF and 6 mL of H2O, was added 0.39 g (9.25 mmol) LiOH.H2O in one portion. The reaction mixture was heated under reflux for 16 h. After the evaporation the mixture was extracted with Et2O (10 mL), and acidified to pH=2-3 with 2 N HCl. The resulting solid was filtered off, washed with water and dried to give 0.65 g of the title compound (intermediate 1) in 97% yield as a white solid. (m/e): 365.1 (MH+; 100%).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH2:9]([N:16]1[C:21](=[O:22])[C:20]2=[C:23]([Cl:26])[CH:24]=[CH:25][N:19]2[N:18]=[C:17]1[CH3:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O-]S([O-])(=O)=O.[Mg+2]>CN(C=O)C>[CH2:9]([N:16]1[C:21](=[O:22])[C:20]2=[C:23]([Cl:26])[CH:24]=[CH:25][N:19]2[N:18]=[C:17]1[CH:27]=[CH:3][N:4]([CH3:6])[CH3:5])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Product: CN(C)C=Cc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Temperature: 140 °C
Yield: 49.8 %

Procedure:
Dimethylformamide dimethylacetal (20 ml, 152 mmol) was added to a solution of 3-benzyl-5-chloro-2-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (9.0 g, 33 mmol) in DMF (100 mL) with MgSO4 (5 g) and the reaction mixture was heated to 140° C. in a sealed tube for 16 h. The reaction mixture was concentrated in vacuo, the residue dissolved with EtOAc (50 mL) and a solid was precipitated by addition of petroleum ether (300 mL). The solid was filtered, washed with petroleum ether and dried in vacuo to afford title compound (5.4 g, 50%) as a solid: 1H NMR (CDCl3) δ 7.22 (d, 1H, J=12.43 Hz), 7.08–7.19 (m, 5H), 6.97 (m, 1H), 6.23 (m, 1H), 5.08 (s, 2H), 4.40 (d, 1H, J=12.49 Hz), 2.67 (s, 6H); MS (ESI+) 329 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)([OH:15])[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)([OH:15])[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:8]
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(O)(c2ccc(F)cc2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(O)(c4ccc(F)cc4)C3)CC2)cc1
Yield: 78.1 %

Procedure:
The title compound (D162) (76.7 mg) was prepared according to the experimental procedure described in Description 146 (reaction time 1 h) starting from 5-chloro-2-(3-(4-fluorophenyl)-3-hydroxyazetidin-1-yl)nicotinic acid (D112) (64 mg, 0.198 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (45 mg, 0.198 mmol).
Reaction SMILES: [CH2:1]([N:4]([CH2:26][CH:27]=[CH2:28])[C:5](=[O:25])[C:6]1[C:20]([I:21])=[C:19]([NH2:22])[C:18]([I:23])=[C:8]([C:9]([N:11]([CH2:15][CH:16]=[CH2:17])[CH2:12][CH:13]=[CH2:14])=[O:10])[C:7]=1[I:24])[CH:2]=[CH2:3].[C:29](Cl)(Cl)=[O:30].C1(C)C=CC=CC=1>O1CCOCC1>[CH2:1]([N:4]([CH2:26][CH:27]=[CH2:28])[C:5](=[O:25])[C:6]1[C:20]([I:21])=[C:19]([N:22]=[C:29]=[O:30])[C:18]([I:23])=[C:8]([C:9]([N:11]([CH2:15][CH:16]=[CH2:17])[CH2:12][CH:13]=[CH2:14])=[O:10])[C:7]=1[I:24])[CH:2]=[CH2:3]
Reactant: O=C(Cl)Cl
Reactant: C=CCN(CC=C)C(=O)c1c(I)c(N)c(I)c(C(=O)N(CC=C)CC=C)c1I
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: C=CCN(CC=C)C(=O)c1c(I)c(N=C=O)c(I)c(C(=O)N(CC=C)CC=C)c1I
Temperature: 60 °C

Procedure:
To a solution of N,N,N′,N′-tetraallyl-5-amino-2,4,6-triiodo-isophthalamide (5 g, 7 mmol) in 1,4-dioxane (10 mL) was added ˜11 equivalents of 20% phosgene solution in toluene (35 mL, 70 mmol) at ambient temperature. The flask was sealed and the solution was heated at 60° C. for 15 hours. The reaction was allowed to cool to ambient temperature and then concentrated at reduced pressure to yield an off white, semi-crystalline solid. Dioxane (50 mL×2) was added and removed slowly at reduced pressure to give an off white, semi-crystalline solid which was placed on a vacuum line to remove any residual solvent. The material was used without further purification.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=[O:18])[CH:9]=1)[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:23]O>>[NH2:2][CH:3]([CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=[O:18])[CH:9]=1)[C:4]([O:6][CH3:23])=[O:5]
Reactant: NC(Cc1cc(=O)[nH]c2ccccc12)C(=O)O
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)Cc1cc(=O)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 Grams of 2-amino-3-(2-quinolon-4-yl)propionic acid hydrochloride was suspended in 50 ml of methanol. Under an ice-cooled condition with strring, 5.3 g of thionyl chloride was added dropwise thereto, the reaction mixture was stirred at a room temperature overnight. Methanol and thionyl chloride were removed by distillation under a reduced pressure, then the residue obtained was recrystallized from methanolacetone to obtain 2.4 g of methyl 2-amino-3-(2-quinolon-4-yl)propionate in the form of white powdery product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:16]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: COCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCCOS(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of 2-(2-methoxyethoxy)ethanol (200 mg, 1.67 mmol, 1 equiv.), triethylamine (232 μL, 1.67 mmol, 1.0 equiv.) and tosyl chloride (317 mg, 1.67 mmol, 1 equiv.) in methylene chloride (5 mL, 0.29 M) was stirred at room temperature for 50 hours. After removal of the solvent under reduced pressure, the residue was purified by chromatography on silica gel (10 g, hexanes/EtOAc 9:1 to 1:1) to afford (2-methoxyethoxy)ethyl 4-methylbenzenesulfonate as a colorless oil (260 mg, 457 mg theoretical, 56.9%). LC-MS m/z 275 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 5 h
Yield: 85 %

Procedure:
tert-Butyl 4-hydroxymethylpiperidine-1-carboxylate (prepared by referring to Japanese Patent Unexamined Publication No. 11-217377, 12.12 g, 56.30 mmol) was dissolved in dichloromethane (26 ml), and the solution was added with p-toluenesulfonyl chloride (10.73 g, 56.30 mmol) and triethylamine (8.63 mmol, 61.9 mmol) at room temperature, and then stirred at the same temperature for 5 hours. The reaction mixture was diluted with dichloromethane (100 ml) and washed with water and saturated brine, and dried over sodium sulfate. Insoluble solids were removed by filtration and the filtrate was evaporated under reduced pressure. The residue was recrystallized from hexane (100 ml) to obtain the title compound as colorless solid (14.13 g, yield: 85%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:3]=1.[C:19]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:32]2[CH2:31][CH2:30][N:29]([C:19]3[C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH2:34][CH2:33]2)[N:5]=[C:6]2[C:11]=1[CH2:10][CH2:9][C:8](=[O:12])[NH:7]2
Reactant: c1cc2c(c(N3CCNCC3)c1)CCCC2
Reactant: Cc1cc(OCCCC=O)nc2c1CCC(=O)N2
Product: Cc1cc(OCCCCN2CCN(c3cccc4c3CCCC4)CC2)nc2c1CCC(=O)N2

Procedure:
The title compound was prepared by reductive amination of 4-(4-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde with 1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine according to the above procedure. MS: APCI: M+1: 450.0 (Exact Mass: 448.28).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([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)[C:7]=2[O:6][CH2:5]1.C(N(CC)C(C)C)(C)C.[C:37](O)(=[O:39])[CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([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][C:37](=[O:39])[CH3:38])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (Intermediate A) (50 mg, 0.136 mmol) in DMF (1 ml) was added N,N-diisopropylethylamine (62 mg, 0.0831 ml, 0.476 mmol), acetic acid (9.8 mg, 9.33 μl, 0.163 mmol) and TBTU (52.4 mg, 0.163 mmol). The mixture was allowed to stir at room temperature for 4 h and poured into ice/water (0.5 ml). The crude reaction mixture was concentrated in vacuo. The reaction mixture was solved with sat NaHCO3 (1×10 mL). and extracted with dichloromethane (2×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 100 g, 0% to 20% MeOH in dichloromethane) to yield the title compound as an off-white solid (53 mg, 62%), MS (ISP) m/z=374.3 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:13][C:14]([NH:16][C@@H:17]([CH2:20][CH2:21][S:22][CH3:23])[CH:18]=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:9]([O:13][C:14]([NH:16][C@@H:17]([CH2:20][CH2:21][S:22][CH3:23])[CH2:18][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1)=[O:15])([CH3:10])([CH3:12])[CH3:11]
Reactant: Nc1cccc(Cl)c1
Reactant: CSCC[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CSCC[C@@H](CNc1cccc(Cl)c1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 3-chloroaniline (10.3 mL, 97.4 mmol), the product from Step G (23.9 g, 97.4 mmol), and acetic acid (27.8 mL, 487 mmol) in dichloroethane (250 mL) under nitrogen was added sodium triacetoxyborohydride (41.3 g, 195 mmol). The reaction was stirred overnight, then quenched with saturated sodium bicarbonate solution. The solution was diluted with CHCl3, and the organic phase was washed with water, 10% citric acid and brine. The solution was dried over sodium sulfate and concentrated in vacuo to provide the crude product (34.8 g) which was chromatographed on silica gel with 20% ethyl acetate in hexane to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20]Cl)=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[NH:22]1[CH2:32][CH2:31][CH:25]([C:26]([O:28][CH2:29]C)=[O:27])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:22]3[CH2:32][CH2:31][CH:25]([C:26]([O:28][CH3:29])=[O:27])[CH2:24][CH2:23]3)=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: ClCCCOc1ccc(-n2nc3ccccc3c2Cl)cc1
Reactant: CCOC(=O)C1CCNCC1
Product: COC(=O)C1CCN(CCCOc2ccc(-n3nc4ccccc4c3Cl)cc2)CC1
Yield: 81.8 %

Procedure:
The title compound was prepared 3-chloro-2-[4-(3-chloro-propoxy)-phenyl]-2H-indazole (0.5 g, 1.6 mmol) and ethyl isonipecotate (0.37 g, 2.3 mmol) using the procedure of step 4 of the Example 4 to provide the title compound (0.56 g, 75%) as a hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([NH2:28])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[O:29]1[CH2:32][C:31](=O)[CH2:30]1>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([NH:28][CH:31]5[CH2:32][O:29][CH2:30]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Nc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Reactant: O=C1COC1
Solvent: C1CCOC1
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(NC4COC4)ccc2OCC3)c(F)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Compound 134 (200 mg, 0.5 mmol) was dissolved in THF, and oxetan-3-one (252 mg, 0.35 mmol) was added at 0° C. The mixture was warmed to 80° C. and stirred for 0.5 h at this temperature. It was cooled to 0° C., NaBH(CN)3 (67 mg, 0.6 mmol) was added. Then the mixture was warmed to 80° C. and stirred for further 0.5 h at this temperature. The reaction mixture was filtered to gather the solution. Then water was added into the solution. It was extracted by DCM (20 mL×3). The combined organics were dried over Na2SO4, concentrated in vacuo, and separated by prep TLC (EtOAc/hexanes=4:1) to give 434 (115 mg, yield: 50%). 1H NMR (DMSO-d6, 400 MHz): δ9.42 (s, 1H), 8.42 (s, 1H), 8.00-7.49 (m, 4H), 7.12 (s, 1H), 7.04 (d, J=9.6 Hz, 1H), 4.85-4.83 (m, 1H), 4.58-4.38 (m, 4H), 3.65 (t, J=6.4 Hz, 2H), 2.93 (t, J=6.4 Hz, 2H). LC-MS (ESI): m/z=454 [M+H]+
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@H:5]1[O:17][CH3:18])=[N+:2]=[N-:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]([C@@H:4]1[CH2:9][CH2:8][NH:7][CH2:6][C@H:5]1[O:17][CH3:18])=[N+:2]=[N-:3]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N=[N+]=[N-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@@H]1CNCC[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 206.4 %

Procedure:
To a stirred solution of 247A (310 mg, 1.21 mmol) in 2 mL of CH2Cl2 at room temperature was added TFA (2.00 mL, 26.0 mmoL). This mixture was stirred at room temperature for 15 min and concentrated in vacuo to give 390 mg of (3R,4R)-rel-4-azido-3-methoxypiperidine as the TFA salt. Compound 247B was prepared from this TFA salt (52.0 mg, 0.19 mmoL) in a similar process as described for 146E. It had an analytical HPLC retention time=1.97 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10–90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=409.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>[OH-].[Na+].C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 mmoles (16.51 grams) of (L)-phenylalanine were dissolved in 50 ml of 2N NaOH, cooled in an ice bath and treated dropwise with 106 mmoles (15.04 ml) of benzyl chloroformate. Stirring at room temperature was carried out for 30 minutes. If the product precipitates out already, sufficient water is added thereto until a clear solution is attained. 4N Hydrochloric acid is dropped in until acid reaction (pH4) and shaken three times with ethyl acetate. The organic phases were dried over sodium sulfate and freed from solvent in a vacuum. There was obtained a colorless, oily product. It was dissolved in 200 ml of chloroform, precipitated in the cold by addition of 400 ml of petroleum ether and filtered off with suction in a large suction filter. Colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[CH2:28]([S-:30])[CH3:29].[Na+]>O1CCOCC1.CN(C=O)C>[CH2:28]([S:30][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[CH3:29]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCSc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium ethanethiolate in dioxane and DMF. ES-MS m/e (%): 431 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=O)[CH:8]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][CH2:40][C@H:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1>C(Cl)Cl>[CH2:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:51][CH2:52][N:43]1[CH2:42][C@@H:41]([OH:53])[CH2:40][NH:39][C:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)=[O:14]
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Reactant: Cc1ccc2cc(C(=O)O)ccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2cc(C(=O)NC[C@H](O)CN3CCc4ccccc4C3)ccc2n1
Temperature: 15 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
To a solution of 2-methylquinoline-6-carboxylic acid (1 g, 5.35 mmol) in DCM (100 mL), was added HATU (2.44 g, 6.42 mmol) and TEA (1620 mg, 16.043 mmol). The solution was stirred at 15° C. for 30 minutes before (S)-1-amino-3-(3,4-dihydro isoquinolin-2(1H)-yl)propan-2-ol (1.76 g, 8.55 mmol) was added. The resulting solution was stirred for 16 h at 15° C. until LCMS analysis showed the reaction to be complete. The mixture was then concentrated under vacuum and the residue purified by Preparative HPLC to give the desired title compound (502.1 mg, 25%). 1H NMR (400 MHz, METHANOL-d4) δ 8.31 (br. s., 1H), 8.08 (d, J=8.8 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.17-7.03 (m, 4H), 4.23-4.11 (m, 1H), 3.78 (br. s., 2H), 3.59 (d, J=5.5 Hz, 2H), 2.91 (br. s., 4H), 2.78-2.69 (m, 5H). LCMS (m/z): 376.1 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([NH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[O:26])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: NC1CCc2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Product: CC(C)(C)OC(=O)NCCCC(=O)NC1CCc2ccccc2NC1=O

Procedure:
Prepared from 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step A) and 4-(t-butoxycarbonylamino)butyric acid by the procedure described in Example 25, Step A. 1H NMR (200 MHz, CDCl3): 1.42 (s,9H), 1.7-2.1 (m,3H), 2.24 (t,5 Hz,2H), 2.58-3.29 (m,5H), 4.57 (m,1H), 4.86 (br s,1H), 7.0-7.3 (m,4H), 8.32 (s,1H). FAB-MS: calculated for C19H27N3O4 361; found 362 (M+H,60%).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]=[CH:13][CH:14]=1)([O-])=O.[Cl-].[NH4+:29].C(O)C>O>[NH2:29][C:25]1[CH:26]=[CH:27][CH:4]=[CH:5][C:6]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]=[CH:13][CH:14]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1occc1-c1cccc(OCc2cccc([N+](=O)[O-])c2)c1
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1occc1-c1cccc(OCc2ccccc2N)c1
Yield: 78.8 %

Procedure:
A mixture of ethyl 3-[3-(3-nitrobenzyloxy)phenyl]-2-furancarboxylate (2.21 g), reduced iron (1.75 g), ammonium chloride (0.67 g), ethanol (30 ml) and water (10 ml) was heated at reflux for 1 hour. After filtering the reaction solution through celite, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/3), thereby giving 1.60 g of ethyl 3-[3-(2-aminobenzyloxy)phenyl)-2-furancarboxylate.