Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[Cl:35])=[N:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]3[O:27][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=4[Cl:35])=[N:25][CH:24]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: Clc1cccc(-c2ncc(CBr)o2)c1Cl
Product: O=c1n(Cc2cnc(-c3cccc(Cl)c3Cl)o2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
49 mg (0.16 mmol) of the compound from Example 5A were reacted with 49 mg (0.16 mmol) of the compound from Example 55A analogously to the preparation of the compound in Example 77. This gave 35 mg (40% of theory) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH2:10][SH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](=O)(OC1C=CC=CC=1)[O:13]C1C=CC=CC=1>C(O)C>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][S:11][C:12]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCCNCc1ccccc1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Solvent: CCO
Product: O=C1SCCN1Cc1ccccc1
Yield: 56.4 %

Procedure:
A solution containing 33.6 g (0.2 mol) of N-phenylmethylcysteamine and 42.8 g (0.2 mol) of diphenyl carbonate in 200 ml of ethanol is refluxed under nitrogen for 24 hours, then ethanol is evaporated under reduced pressure. The residue is taken up in ethyl acetate, washed with 2N sodium hydroxide solution until it becomes free of phenol, then washed with water, dried and evaporated. The residue is distilled under reduced pressure to give 21.8 g (56.4%) of the title compound, b.p.: 140° C./1.5 Hgmm, which solidifies under petroleum ether, m.p.: 50°-51° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([OH:11])=O)=[N:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[C:24]([NH:23][C:9]([C:5]5[C:6]([CH3:8])=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=5)=[O:11])[CH:45]=[CH:44][CH:43]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: CCn1cc(C)c(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: CCn1cc(C)c(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n1
Yield: 52.1 %

Procedure:
In the same manner as in Example 18-4 and using 1-ethyl-4-methyl-1H-pyrazole-3-carboxylic acid (150 mg, 0.970 mmol), tetrahydrofuran (7 mL), oxalyl chloride (93.0 μL, 1.07 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (150 mg, 52%) was obtained as a white solid.
Reaction SMILES: B(F)(F)F.[C:5]([OH:22])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH3:23][C:24]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:25]=1[OH:26].C([O-])(=O)C.[Na+]>O.C(Cl)Cl>[CH3:23][C:24]1[CH:30]=[C:29]([OH:31])[C:28]([C:5](=[O:22])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:27][C:25]=1[OH:26]
Reactant: Cc1cc(O)ccc1O
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)c1cc(O)c(C)cc1O
Reaction time: 8 h

Procedure:
Boron trifluoride was introduced with vigorous refluxing until saturation into a mixture of 27.2 g of palmitic acid, 13.7 g of 2-methylhydroquinone and 45 ml of methylene chloride. After standing overnight the mixture was refluxed for another hour and then decomposed with stirring in a solution of 25 g of sodium acetate in 220 ml of water. After 45 min the solution in methylene chloride was separated and evaporated. The residue was stirred with methanol, filtered with suction and recrystallized from n-chlorobutane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8](O)=[O:9])=[O:4].O1CCCC1.CO>C(OCC)(=O)C>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(CO)cc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
3-(Methoxycarbonyl)-5-nitrobenzoic acid (20.0 g, 88.9 mmol) was combined with tetrahydrofuran (150 mL) and cooled to 0° C. To this solution was added a 1 M borane tetrahydrofuran complex (178 mL, 178 mmol) cautiously over 15 min and the reaction mixture allowed to warm to room temperature overnight. The mixture was cooled to 0° C., treated with excess methanol and concentrated in vacuo to afford to afford a precipitate which was dissolved in ethyl acetate, washed with concentrated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated to afford 18.2 g (97%) which was used without further purification. 1H-NMR (CDCl3, 300 MHz) δ 8.70 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 4.84 (s, 2H), 3.95 (s, 3H). Mass spec.: 212.06 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH2:35][CH:36]2[CH2:40][CH2:39][CH2:38][NH:37]2)=[O:33])=[CH:4][N:3]=1.Cl.CN(CC(Cl)=[O:47])C.[CH:49]([N:52]([CH2:56]C)[CH:53](C)C)(C)[CH3:50]>ClCCl>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH2:35][CH:36]2[CH2:40][CH2:39][CH2:38][N:37]2[CH2:50][C:49]([N:52]([CH3:56])[CH3:53])=[O:47])=[O:33])=[CH:4][N:3]=1
Reactant: CN(C)CC(=O)Cl
Reactant: COc1cc(-c2csc3c(C(=O)NCC4CCCN4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cc(-c2csc3c(C(=O)NCC4CCCN4CC(=O)N(C)C)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)-N-(pyrrolidin-2-ylmethyl)thieno[3,2-c]pyridine-7-carboxamide (0.100 g, 0.18 mmol), dimethylaminoacetyl chloride hydrochloride (0.035 g, 0.217 mmol) and N,N-diisopropylethyl amine (0.046 g, 0.360 mmol) in dichloromethane (2 mL) was stirred at ambient temperature for 1 hour. The mixture was diluted with dichloromethane then extracted with 2N aqueous sodium hydroxide. The layers were separated and the organic solution was concentrated and the residue was purified by flash chromatography on silica gel to provide the title compound: 1H NMR (DMSO-d6, 400 MHz) δ 9.49 (s, 1H), 8.69 (t, 1H), 8.53 (d, 1H), 8.01 (m, 1H), 7.72 (d, 1H), 7.58 (m, 2H), 7.35 (m, 2H), 7.19 (s, 1H), 7.15 (t, 1H), 7.08 (d, 1H), 6.02 (bs, 2H), 4.25 (m, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 3.48 (m, 2H), 3.10 (m, 2H), 2.26 (s, 6H), 1.7–2 (m, 4H); LCMS (Conditions a), Rt 2.75 min.; MS: MH+ 640
Reaction SMILES: [NH2:1][C:2]1([C:14]([OH:16])=[O:15])[CH2:6][CH2:5][N:4](CC2C=CC=CC=2)[CH2:3]1.[H][H]>>[NH2:1][C:2]1([C:14]([OH:16])=[O:15])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: [H][H]
Reactant: NC1(C(=O)O)CCN(Cc2ccccc2)C1
Product: NC1(C(=O)O)CCNC1

Procedure:
According to a particular variant of embodiment of this synthesis process, 1-benzyl-3-pyrrolidinone is treated with an ammoniacal solution of ammonium chloride and of potassium cyanide to obtain (±)-3-amino-1-benzyl-3-cyanopyrrolidine. This compound is then converted by acid or basic hydrolysis to (±)-3-amino-1-benzyl-3-pyrrolidinecarboxylic acid, and lastly a reduction with hydrogen, preferably a catalytic hydrogenolysis, is carried out to obtain (±)-3-amino-3-pyrrolidinecarboxylic acid or (±)-cucurbitine.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N:9]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:18]([CH2:21][C:22](=[O:24])[CH3:23])(=[O:20])[CH3:19]>C(O)(=O)C.Cl.O.C(O)C>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][N:9]=[C:21]([C:22](=[O:24])[CH3:23])[C:18](=[O:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=N[O-]
Reactant: CC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)C(=NNc1ccc(C)cc1)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
To a solution of 4-methylaniline (1000 mg, 9.34 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (774 mg, 11.21 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (2299 mg, 28.04 mmol) and acetylacetone (1215 mg, 12.15 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-[(4-methylphenyl)hydrazono]pentane-2,4-dione (480 mg, 24%).
Reaction SMILES: ON[C:3]([CH:5]1[CH:11]([CH2:12][O:13]C(=O)C)[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:4].[Li+].[OH-:29]>CO.O>[OH:13][CH2:12][CH:11]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:18])=[O:19])[CH:5]1[C:3]([OH:4])=[O:29]
Reactant: [OH-]
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(COC(C)=O)C2C(=O)NO)cc1
Agent: [Li+]
Solvent: CO
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CCCCC(CO)C2C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
To a solution of Acetic acid 2-hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-azepan-3-ylmethyl ester in 1.1 mL methanol was added 0.1 mL of 1.0 M LiOH in water at ambient temperature. The reaction was stopped after 30 minutes by evaporating the solvent under reduced pressure. The residue was taken up in water and washed twice with diethyl ether, followed by acidification of the water to pH=1 with 1N HCl. The water layer was extracted twice with ethyl acetate which was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure and was purified with column chromatography (silica: 2% to 8% methanol in dichloromethane) to yeild a thin film which was freeze-dried to yield 3-Hydroxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid hydroxamide as a white lyopholate; MS: (M-H)- =357.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:25][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([C:22]([OH:24])=O)[CH:17]=[CH:16]3.[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][NH:27]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][N:27]1[C:22]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][C:12]3[CH2:11][C:3]4([C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:25][C:13]=3[CH:14]=2)[N:19]=1)=[O:24]
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(O)c1ccc2cc3c(cc2n1)CC1(C3)C(=O)Nc2ncccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(c1ccc2cc3c(cc2n1)CC1(C3)C(=O)Nc2ncccc21)N1Cc2ccccc2C1

Procedure:
A mixture of (±)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carboxylic acid (10 mg, 0.030 mmol, described in Intermediate 19), isoindoline (7 mg, 0.060 mmol), EDC (9 mg, 0.045 mmol), HOBT (7 mg, 0.045 mmol), and N,N-diisopropylethylamine (0.026 mL, 0.151 mmol) was stirred in DMF (1 mL) at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3 CN:CF3 CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated to give the title compound. MS: m/z=433 (M+1). HRMS: m/z=433.1667; calculated m/z=433.1659 for C27H21N4O2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH3:12].[K+].[Br-].BrCC[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>C(#N)C>[Br-:10].[CH2:20]([N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:26]2[C:27]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:23]=[CH:24][C:25]=2[CH2:11][CH3:12])[CH:4]=1)[CH2:19][CH2:18][CH2:27][CH3:26]
Reactant: CCBr
Reactant: BrCCc1cccc2ccccc12
Reactant: Clc1nc[nH]c1Cl
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCC[n+]1cn(-c2c(CC)ccc3ccccc23)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromethane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 1-(2-bromoethyl)naphthalene (9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, and the volatiles will be removed en vacuo resulting in the product.
Reaction SMILES: [O:1]([CH2:8][CH:9]([NH2:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]1[N:17]=[C:16](Cl)[C:15]2[N:19]=[CH:20][N:21]([C@@H:22]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:24]([OH:29])[C@H:23]3[OH:30])[C:14]=2[N:13]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[O:1]([CH2:8][CH:9]([NH:11][C:16]1[C:15]2[N:19]=[CH:20][N:21]([C:14]=2[N:13]=[CH:12][N:17]=1)[C@@H:22]1[O:26][C@H:25]([CH2:27][OH:28])[C@@H:24]([OH:29])[C@H:23]1[OH:30])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: CC(N)COc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(COc1ccccc1)Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
1-Phenoxy-2-propylamine (0.33 g, 2.18 mmol) was reacted with 6-chloropurine riboside (i.e. 9-β-D-ribofuranosyl-9H-purine)(0.5 g, 1.7 mmol) in dioxan (30 ml) in the presence of diisopropylethylamine (0.28 g, 2.2 mmol). The reaction mixture was heated at reflux for 5 h, cooled and evaporated. The residue was purified by flash chromatography on silica gel to provide the N-(1-Phenoxy-2-propyl)adenosine (a mixture of diastereoisomers) as a foam (0.06 g, 7%), 1H NMR (DMSO-d6)δ 1.32 (3H, d, --CH3), 3.52-3.60 (1H, m, H-5'a), 3.64-3.71 (1H, m, H-5'b), 3.93-3.99 and 4.12-4.20 (4H, 2m, m, H-4', H-3' and --CH2 --), 4.62 (1H, q, H-2'), 4.68-4.82 (1H, m, --C HCH3), 5.40 (1H, t, 5'-0H), 5.20, 5.45 (2H, 2d, 2'- and 3'-OH), 5.90 (1H, d, H-1'), 6.88-6.98 (3H, m, Ar--H), 7.23-7.31 (2H, t, Ar--H), 7.85, 8.21, 8.38 (3H, 3s, H-2, H-8 and N--H).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[F:22])=[O:13])=[CH:7][CH:6]=1)C.O.[OH-].[Li+].O>CCO.C1COCC1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12](=[O:13])[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:23])=[O:3])=[CH:6][CH:7]=2)=[C:16]([F:22])[CH:17]=1
Reactant: CCOC(=O)c1ccc(NC(=O)Nc2ccc(Br)cc2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.5 %

Procedure:
To a solution of 4-[3-(4-bromo-2-fluoro-phenyl)-ureido]-benzoic acid ethyl ester (0.7 g, 0.0018 mol) in EtOH (5 mL) and THF (4 mL), was added a solution of lithium hydroxide monohydrate in water (0.385 g, 0.009 mol, in 5 mL water) at room temperature. The reaction mass was stirred at room temperature for 5 h. The volatiles were evaporated under reduced pressure. The white solid was washed with diethyl ether. Subsequently, the reaction mixture was acidified with 2 N HCl [pH-6] at 0° C. to afford the solid compound. The solid material was collected by filtration and dried to obtain the title compound [0.55 g, 84%]; LC-MS (ESI): Calculated mass: 352.0; Observed mass: 352.9 [M+H]+ (RT: 1.49 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]=[C:5](NC)[CH3:6].N1C=CC=CC=1.[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.[OH2:26]>C1COCC1>[CH3:1][O:2][C:3](=[O:9])[CH:4]([C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([Br:16])=[CH:18][CH:19]=1)[C:5](=[O:26])[CH3:6]
Reactant: CNC(C)=CC(=O)OC
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)C(C(C)=O)C(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 3-methylamino-but-2-enoic acid methyl ester (5.0 g, 39.1 mmol) in THF (70 mL) was added pyridine (3.7 mL, 47 mmol) dropwise. The mixture was cooled to 0° C., and 4-bromobenzoyl chloride (8.55 g, 39.1 mmol) in THF (30 mL) was added dropwise. The reaction was stirred at room temperature overnight, and then water was added. The mixture was extracted with EtOAc, and the combined organic layers were washed with water, dried, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([O:12][CH3:13])[CH:4]=1.[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][C:8]1[CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c([N+](=O)[O-])cc1Br
Temperature: 25 °C

Procedure:
1,3-Dimethoxy-4-nitrobenzene (5.0 g, 27 mmol) in chloroform (50 ml) at 0° C., was treated with a solution of bromine (1.68 ml, 33 mmol) in chloroform (50 ml). The solution was stirred with warming to room temperature for 4 hours, washed with 10% sodium thiosulfate solution and brine then dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was used without further purification (D17). MS (ES+) m/e 262/264 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]#[N:19])=[CH:12][CH:11]=3)#[N:4].[CH2:20](Br)[CH2:21][CH2:22][CH3:23].O>CN(C)C=O>[CH2:20]([N:9]1[C:10]2[CH:11]=[CH:12][C:13]([C:18]#[N:19])=[CH:14][C:15]=2[C:16]2[C:8]1=[CH:7][CH:6]=[C:5]([C:3]#[N:4])[CH:17]=2)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCBr
Reactant: N#Cc1ccc2[nH]c3ccc(C#N)cc3c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1c2ccc(C#N)cc2c2cc(C#N)ccc21
Temperature: 110 °C
Yield: 81.3 %

Procedure:
A slurry of sodium hydride (50% in oil, 480 mg) in 50 ml of anhydrous dimethylformamide is treated with 3,6-dicyanocarbazole (2.17 g) and heated at 110° C for two hours. The reaction mixture is then treated dropwise with butylbromide (1.37 g) and heated for about 16 hours at 110° C. The reaction mixture is poured into water and the resultant precipitate collected by filtration. The solid is dissolved in dichloromethane and filtered through 200 ml of silica gel to yield 2.22 g of the title compound, melting point 215°-217°C.
Reaction SMILES: Cl[CH2:2][O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[C@@:8]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])([F:19])[C:7]1=[O:29])=[O:5].[I-:30].[Na+]>CC(C)=O>[I:30][CH2:2][O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[C:8]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])([F:19])[C:7]1=[O:29])=[O:5]
Reactant: [I-]
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCCl)c2cc(C(F)(F)F)ccc21
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1C1(F)C(=O)N(C(=O)OCI)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.1 %

Procedure:
To a 25 mL flask containing (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid chloromethyl ester ((S)-XII) (0.633 g, 1.40 mmol) was added 6 mL anhydrous acetone, and sodium iodide (0.314 g, 2.10 mmol). The reaction was heated to reflux and stirred for 4 hours, then the reaction was cooled to room temperature, and the solvent was evaporated in vacuo. The crude oil was dissolved in dichloromethane and washed with a 1% aq. sodium thiosulfate solution. The organic layer was separated, dried (Na2SO4) and evaporated in vacuo producing the title compound (0.640 g, 84%) which was used in subsequent reactions without purification. 1H NMR (CDCl3 400 MHz): δ=8.38 (s, 1H), 7.78 (s, 1H), 7.48 (d, 1H, J=7 Hz), 7.36 (d, 1H, J=7 Hz), 7.31 (d, 1H, J=7 Hz), 6.77 (d, 1H, J=7 Hz), 6.28 (d, 1H, J=6.4 Hz), 6.18 (d, 1H, J=6.4 Hz), 3.56 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([N:14]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:17]2[CH2:18][CH2:19][CH2:20][N:14]([C@@H:10]3[CH2:9][NH:8][CH2:12][C@H:11]3[OH:13])[CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N2CCCN(c3ccc(Cl)cc3)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O[C@@H]1CNC[C@H]1N1CCCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 151.2 %

Procedure:
To a solution of trans-3-[4-(4-Chloro-phenyl)-[1,4]diazepan-1-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.820 g, 2.08 mmol) in methylene chloride (1 mL) was added 4 N HCl/dioxane (10 mL, 40 mmol). The solution was stirred at rt for 1 hour, upon which a brown precipitate formed. The reaction was concentrated in vacuo to yield 0.930 g (−100%) of the title compound. ESI-MS m/z: 296 (M+1), FAS method rt: 0.83 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.[F:10][C:11]([F:23])([F:22])[C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH2:18][NH:19]2)=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:19]1[C:20]2[C:15](=[CH:14][CH:13]=[C:12]([C:11]([F:10])([F:22])[F:23])[CH:21]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: BrCc1cccc(Br)c1
Reactant: FC(F)(F)c1ccc2c(c1)NCCC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1ccc2c(c1)N(Cc1cccc(Br)c1)CCC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Under a nitrogen atmosphere, a solution of bromo-3-bromomethyl-benzene (3.47 g, 13.p mmol) and 7-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (2.93 g, 14.6 mmol) in ethanol (15 mL, 1 M) was treated with sodium acetate (5.69 g, 69.3 mmol) and heated to 80° C. After stirring 2 h, the solution was cooled to room temperature, diluted with water, extracted with ethyl acetate and washed with saturated aq sodium chloride. The organic layer was dried over MgSO4, filtered and concentrated. Purification by column chromatography (10% ethyl acetate in heptane) provided 1-(3-bromo-benzyl)-7-trifluoromethyl-1,2,3,4-tetrahydro-quinoline 4.21 g (82%) as a colorless oil.
Reaction SMILES: C1COCC1.CO.C[Si]([C:12]#[C:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>O>[C:13]([C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1)#[CH:12]
Reactant: C[Si](C)(C)C#Cc1ccc(N)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C#Cc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of THF (1 mL) and methanol (1 mL) of 5-trimethylsilanylethynyl-pyridin-2-ylamine (26 mg) described in Manufacturing Example 3-2 was added potassium carbonate (38 mg) at room temperature, which was stirred for 1 hour at room temperature. Water was added at 0° C. to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the solvent was evaporated from the filtrate under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the titled compound (16 mg).