Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:14]([O:17][CH3:18])=[N:15][CH:16]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25].N1C=CC=CC=1.[Cl:39][CH2:40][C:41]1[N:46]=[C:45]([C:47](Cl)=[O:48])[CH:44]=[CH:43][CH:42]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:39][CH2:40][C:41]1[N:46]=[C:45]([C:47]([NH:1][C:2]2[CH:10]=[C:9]([C:11]3[CH:16]=[N:15][C:14]([O:17][CH3:18])=[C:13]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:12]=3)[CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][N:6]3[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[O:48])[CH:44]=[CH:43][CH:42]=1
Reactant: COc1ncc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Reactant: O=C(Cl)c1cccc(CCl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ncc(-c2cc(NC(=O)c3cccc(CCl)n3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
N-[5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (750 mg, 1.584 mmol) was dissolved in DCM (20 ml), cooled to 0° C. before pyridine (0.192 mL, 2.376 mmol) was added. 6-(chloromethyl)-2-pyridinecarbonyl chloride (354 mg, 1.584 mmol) in DCM (10 ml) was then added dropwise over 15 mins and the reaction was stirred at 0° C. for 2 hr; ice was allowed to melt over this time. Saturated aqueous sodium bicarbonate solution (20 ml) was added to the mixture and it was stirred vigourously for 10 mins. The organic layer was separated using a hydrophobic frit, washed with water (20 ml) and concentrated in vacuo to give an orange oil. The oil was triturated with ether and the resulting solid was filtered off then pre-adsorbed onto silica. The silica was added to the top of a 50 g silica SPE cartridge that was subsequently eluted with 0-100% EtOAc/cyclohexane over 60 mins to afford the title compound as a pale yellow solid (253 mg).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([O:7][C:8]2[C:9](=[O:22])[N:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:11]=[CH:12][C:13]=2Cl)=[CH:3][CH:2]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([C:13]1[CH:12]=[N:11][N:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:9](=[O:22])[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][C:1]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:2][CH:3]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1c(Oc2ccc(-c3ccccc3)cc2)c(Cl)cnn1-c1ccc(Cl)cc1
Agent: [Na+]
Product: [N-]=[N+]=Nc1cnn(-c2ccc(Cl)cc2)c(=O)c1Oc1ccc(-c2ccccc2)cc1

Procedure:
Obtainable by general method 13 from 2.05 g (5.0 mmol) of the compound from Example 9A with 1.63 g (25.0 mmol) of sodium azide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=2)[N:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=2)[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])nn1Cc1cc(F)c(F)c(F)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)nn1Cc1cc(F)c(F)c(F)c1
Reaction time: 1.5 h
Yield: 7.8 %

Procedure:
To a suspension of 5-nitro-2-(3,4,5-trifluoro-benzyl)-2H-pyrazole-3-carboxylic acid methyl ester (649 mg, 2.1 mmol) in 12 ml of methanol was added 100 mg of palladium 10% on charcoal and the mixture hydrogenated for 1.5 hours at room temperature and normal pressure. The catalyst was filtered off and the filtrate concentrated to yield the title compound as a colorless solid (47 mg, Yield=80%). MS ISP (m/e): 286.0 (100) [(M+H)+].
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH3:21]>O>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[N:3]1[CH2:20][CH3:21]
Reactant: Cc1ccc2c(c1)NC(C)CC2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCN1c2cc(C)ccc2CCC1C
Yield: 77.6 %

Procedure:
A mixture of 2,7-dimethyl-1,2,3,4-tetrahydroquinoline (48.3 g. 0.3 m), potassium carbonate (41.4 g, 0.3 m), and iodoethane (100 g) was heated at reflux for 4 hrs. Water (200 ml) was added and then the organic layer was extracted using chloroform (100 ml). The organic layer was separated and dried over sodium sulfate. Chloroform and excess iodoethane were distilled off to leave essentially pure product (44 g), which was used without further purification.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate (Example Ac, 1.24 g, 5.0 mmol) in POCl3 was refluxed under nitrogen for 3 hrs. The solution was cooled to room temperature and evaporated under reduced pressure. The residue was carefully quenched with ice, and neutralized with 2.0 N NaOH to pH 7. The precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound as a pale-yellow solid (1.29 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ 1.36 (t, J=7.0 Hz, 3H), 3.96 (s, 3H), 4.41 (q, J=7.0 Hz, 2H), 7.57 (d, J=2.8 Hz, 1H), 7.61 (dd, J=2.8, 8.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 8.97 (s, 1H). MS 266, 268 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:18]CC#N)[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:22]([CH3:24])[CH3:23])=[CH:4][CH:3]=1.Cl.[C:26]([OH:32])([C:28](F)(F)F)=[O:27]>CO.[OH-].[K+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:18][CH2:28][C:26]([OH:32])=[O:27])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:22]([CH3:24])[CH3:23])=[CH:6][CH:7]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CCC#N)CCC2
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CCC(=O)O)CCC2
Reaction time: 18 h

Procedure:
A solution of Intermediate 78 (128 mg, two batches) in Methanol (3.5 mL) and potassium hydroxide (10M aqueous soln) (0.749 mL) was heated to reflux overnight. LCMS after 18 h indicated approximately 20% conversion to the acid. Further potassium hydroxide (10M aqueous soln) (0.749 mL was added to the reaction mixture and it was left to heat for a further 36 h. LCMS after this time demonstrated full conversion to the acid product. Aqueous HCl (4.85 mL) was added to the reaction mixture to neutralise to the KOH. The product was extracted from the reaction mixture using EtOAc. The organic layer was washed with water, brine and then dried over MgSO4 and filtered, before being concentrated in vacuo to give the product, 88 mg. LC/MS MH+ 361, Rt 2.02 mins (5 min run, TFA modifier).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.F[C:9]1[CH:10]=[C:11]([C:19]([O:21][CH3:22])=[O:20])[C:12](=[CH:17][CH:18]=1)[C:13]([O:15][CH3:16])=[O:14]>CN1CCCC1=O>[N:3]1([C:18]2[CH:17]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[C:11](=[CH:10][CH:9]=2)[C:19]([O:21][CH3:22])=[O:20])[CH:7]=[CH:6][CH:5]=[N:4]1
Reactant: COC(=O)c1ccc(F)cc1C(=O)OC
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(-n2cccn2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
26 g of oily sodium hydride was added over 40 min to 200 ml solution of 44 g pyrazole in 1-methyl-2-pyrrolidinone. 125 g of dimethyl 4-fluorophthalate was added thereto over 30 min and stirred at room temperature for 2 hr. The reaction solution was cooled to 0° C. and added to ice water. It was extracted with ethyl acetate, and washed with saturated sodium bicarbonate and brine. It was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated, and diethyl ether was added to the resulting crystalline residue which was then collected by filtration to give 77 g of dimethyl 4-(1H-1-pyrazolyl)phthalate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:27])[NH:17][C:18]1[N:19]=[C:20]2[N:24]([CH:25]=1)[CH:23]=[C:22](Br)[S:21]2)=[O:10])[CH:6]([CH3:8])[CH3:7].[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3](=[O:28])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:27])[NH:17][C:18]1[N:19]=[C:20]2[N:24]([CH:25]=1)[CH:23]=[C:22]([C:33]1[CH:34]=[CH:35][C:30]([NH2:29])=[CH:31][CH:32]=1)[S:21]2)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: Nc1ccc(B(O)O)cc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(Br)sc2n1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(-c3ccc(N)cc3)sc2n1)C(C)C

Procedure:
Compound A25 was synthesized from 12b (0.318 mmol) and 4-aminophenylboronic acid (0.477 mmol), following the procedure as described for compound A1, to give compound A25 as a white solid in 29%. MS (ESI, EI+) m/z=485.15 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCOc1ccc(N)c([N+](=O)[O-])c1
Solvent: O
Solvent: c1ccncc1
Product: COCOc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
4-Methoxymethoxy-2-nitroaniline (7.69 g (38.8 mmol)) was dissolved in 19.0 ml of pyridine. To this, p-toluenesulfonyl chloride (8.14 g (42.7 mmol)) was added with stirring at room temperature and the mixture was stirred at room temperature for 18 hours. Then, water (200.0 ml) was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography with chloroform-ethanol (100:1) as eluent, to give 9.46 g (63%) of 4′-methoxymethoxy-2′-nitro-p-toluenesulfonanilide as a yellow oil.
Reaction SMILES: C=C([O:4][C:5](=O)[NH:6][C:7]1[CH:12]=[C:11]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)[CH:10]=[CH:9][C:8]=1[F:22])C.[CH:24]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CN1CCCC1>C1COCC1>[CH:24]1([NH:31][C:5]([NH:6][C:7]2[CH:12]=[C:11]([B:13]3[O:14][C:15]([CH3:21])([CH3:20])[C:16]([CH3:19])([CH3:18])[O:17]3)[CH:10]=[CH:9][C:8]=2[F:22])=[O:4])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C=C(C)OC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccc1F
Reactant: NC1CCCCCC1
Agent: CN1CCCC1
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(F)c(NC(=O)NC3CCCCCC3)c2)OC1(C)C
Temperature: 60 °C
Yield: 77.9 %

Procedure:
Treat a solution of prop-1-en-2-yl(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (0.460 g, 1.432 mmol) in THF (5 mL) with cycloheptylamine (0.195 g, 1.719 mmol) followed by a catalytic amount of 1-methylpyrrolidine (0.012 g, 0.143 mmol) and heat at 60° C. for 2 h. Concentrate the mixture to dryness, add MeCN, collect the solid via filtration and dry to afford the title compound (420 mg, 78%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.50 (dd, J=9, 1.7 Hz, 1H), 8.33 (s, 1H), 7.16 (m, 2H), 6.60 (d, J=7.0 Hz, 1H), 3.64 (m, 1H), 1.80 (m, 2H), 1.50 (m, 10H), 1.26 (s, 12H); MS(ESI) m/z: 377.2 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[CH2:13]([CH2:15][NH2:16])[OH:14]>>[OH:14][CH2:13][CH2:15][NH:16][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1
Reactant: NCCO
Reactant: N#Cc1ccc(OCCBr)cc1
Product: N#Cc1ccc(OCCNCCO)cc1
Temperature: 120 °C

Procedure:
4-(2-Bromoethoxy)benzonitrile (30 g, 0.133 mol; see step (i) above) and ethanolamine (48 mL, 0.78 mol) were mixed and refluxed, under a nitrogen atmosphere, at about 120° C. for 3 h. The reaction was quenched by addition of a sodium hydroxide solution to the mixture. The sub-title compound was extracted using DCM (2×250 mL), which was dried over anhydrous sodium sulfate and then concentrated. Yield: 13.1 g (48%).
Reaction SMILES: [CH2:1]([C:3]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:24])[CH:18]=1)([C:6]1[S:10][C:9]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:3]([CH2:4][CH3:5])([C:6]2[S:10][C:9]3[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=3[CH:7]=2)[CH2:1][CH3:2])=[CH:18][C:19]=1[CH3:24]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc2ccc(OC)cc2s1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCC(CC)(c1ccc(OCC(=O)OC)c(C)c1)c1cc2ccc(OC)cc2s1
Yield: 48.9 %

Procedure:
To a mixture of 4-[1-ethyl-1-(6-methoxy-benzo[b]thiophen-2-yl)-propyl]-2-methyl-phenol (2.53 g, 7.43 mmol) and acetonitrile (25 mL) is added methyl bromoacetate (0.84 mL, 8.92 mmol), powdered potassium carbonate (4.10 g, 29.72 mmol), and potassium iodide (0.12 g, 0.74 mmol). The resulting slurry is stirred at reflux temperature for 2 h, filtered, and concentrated. The residue is dissolved in diethyl ether (100 mL), washed with water (75 ml), brine (75 mL), dried over MgSO4, filtered, and concentrated to give the title compound (1.5 g, 3.63 mmol, 49%). 1H NMR (CDCl3), δ 0.74 (t, J=7.2 Hz, 6H), 2.17 (q, J=14.7, 7.5 Hz, 4H), 2.25 (s, 3H), 2.30 (s, 2H), 3.80 (s, 3H), 3.86 (s, 3H), 3.60 (d, J=8.6 Hz, 1H), 6.89 (dd, J=8.6, 2.5 Hz, 1H), 7.04 (s, 1H), 7.07 (s, 1H), 7.16 (d, J=2.5 Hz, 1H), 7.55 (d, J=8.9 Hz, 1H).
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15](=O)[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.[CH3:22][O:23][NH2:24].N1C=CC=CC=1>C(O)C>[CH3:22][O:23][N:24]=[C:15]([C:13]1[S:14][C:10]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)=[CH:11][CH:12]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCC(=O)c1ccc(-n2cnc3ccccc32)s1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCCCC(=NOC)c1ccc(-n2cnc3ccccc32)s1

Procedure:
To the solution of compound (84) (0.703 mmoles) in Ethanol (10 ml) was added N-methoxy amine HCl (2.878 m.moles) and Pyridine (2.844 m.moles) at ambient temp. The reaction mass was heated to reflux for 2.0 hrs. After completion of reaction, distilled off the solvent completely, added Water (20 ml) and the product was extracted in ethyl acetate (2×100 ml), washed with 10% brine and dried over sodium sulphate. The solvent was distilled completely under reduced pressure to get the crude compound. This crude compound was purified by preparative HPLC to get the pure isomers (88 & 89).
Reaction SMILES: [C-:1]#[N:2].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][CH:12]=1)=[O:10]>CS(C)=O>[C:5]1([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:1]#[N:2])=[CH:13][CH:12]=2)=[O:10])[S:4][CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: O=C(c1ccc(CCl)cc1)c1cccs1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc(C(=O)c2cccs2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 5.9 parts of sodium cyanide in 40 parts of dimethyl sulfoxide is heated to 60° C and there are added at once 9.5 parts of α-chloro-p-tolyl 2-thienyl ketone (exothermic reaction: temperature rises to 100° C). The whole is stirred for 2 hours at 60° C. After cooling, the reaction mixture is poured onto water and the product is extracted three times with 450 parts of chloroform. The combined extracts are washed twice with 200 parts of water, dried and evaporated. The dark-coloured residual tar is extracted five times with ether; the combined ether extracts are stirred with activated charcoal, filtered and evaporated. The residue is triturated in petroleumether (solid carbon dioxide) and the whole is evaporated, yielding 2-[p-(2-thenoyl)phenyl]acetonitrile as a residue.
Reaction SMILES: COC[O:4][C@H:5]1[CH2:9][N:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:7]([CH2:20][N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][O:24][C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]2=3)[CH2:6]1.Cl>CO>[OH:4][C@H:5]1[CH2:9][N:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:7]([CH2:20][N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][O:24][C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]2=3)[CH2:6]1
Reactant: COCO[C@@H]1C[C@H](CN2c3ccccc3COc3ccccc32)N(CCc2ccc(OC)cc2)C1
Agent: Cl
Solvent: CO
Product: COc1ccc(CCN2C[C@H](O)C[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Yield: 79.3 %

Procedure:
4.20 g (8.85 mmol) of (+)-5,11-dihydro-5-[[(2R,4R)-4-(methoxymethoxy)-1-(4-methoxyphenethyl)pyrrolidin-2-yl]methyl]dibenzo[b,e][1,4]oxazepine in 40 ml of methanol was treated with 20 ml of 10% HCl for 1 hour under reflux. Methanol was removed in vacuo and 1N NaOH was added to the residue. The products were extracted with ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (ethyl acetate) to give 3.02 g (79.3%) of (+)-5,11-dihydro-5-[[(2R, 4R)-4-hydroxy-1-(4-methoxyphenethyl)pyrrolidin-2-yl]methyl]dibenzo[b,e][1,4]oxazepine as pale yellow amorphous.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].Br[CH2:12][CH:13]1[O:18][CH:17]([CH3:19])[CH:16]([CH3:20])[CH2:15][O:14]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][CH2:12][CH:13]1[O:18][CH:17]([CH3:19])[CH:16]([CH3:20])[CH2:15][O:14]1)[CH3:2]
Reactant: CCOC(CCN)OCC
Reactant: CC1COC(CBr)OC1C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(CCNCC1OCC(C)C(C)O1)OCC
Temperature: 25 °C

Procedure:
3,3-Diethoxypropylamine (0.11 mole), 2-bromomethyl-4,5-dimethyl-1,3-dioxane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(3,3-diethoxypropyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)amine.
Reaction SMILES: CC[N:3]=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.[NH2:23][C:24]1[C:32]([I:33])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].O.N>CN(C=O)C.O>[NH2:23][C:24]1[C:32]([I:33])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH2:3])=[O:27]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1c(I)cccc1C(=O)O
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(I)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
EDCI hydrochloride (18.4 g) and 1-hydroxybenzotriazole (9.5 g) were added to a solution of 2-amino-3-iodobenzoic acid (16.4 g) synthesized using the method described in Journal of Medicinal Chemistry, 2004, 47 (6), 1448-1464 in DMF (120 mL), and subsequently ammonia water (21.2 ml) was added thereto. The reaction solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the deposit was filtrated and dried under reduced pressure to obtain 2-amino-3-iodobenzamide (12.8 g). 60% sodium hydride (2.29 g) was added to a solution of the obtained 2-amino-3-iodobenzamide (5.0 g) in ethanol (95 ml), then ethyl trifluoroacetate (10.8 g) was added thereto, and the mixture was heated to reflux for 15 hours. After cooling, water was added thereto, and the reaction solution was rendered acidic by the addition of 6 N hydrochloric acid. Then, the deposit was filtrated and dried under reduced pressure to obtain compound (4a) (6.4 g, yield based on 2 steps: 77%).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:15][C:8]2=[N:9][C:10]([CH3:14])=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH3:4].[Br:16][C:17]1[CH:18]=[N:19][C:20]2[CH:21](Cl)[CH2:22][CH2:23][C:24]=2[CH:25]=1.[Na+].[Br-]>O1CCOCC1>[Br:16][C:17]1[CH:18]=[N:19][C:20]2[CH:21]([N:15]3[C:8]4=[N:9][C:10]([CH3:14])=[CH:11][C:12]([CH3:13])=[C:7]4[N:6]=[C:5]3[CH2:3][CH3:4])[CH2:22][CH2:23][C:24]=2[CH:25]=1
Reactant: ClC1CCc2cc(Br)cnc21
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCc1nc2c(C)cc(C)nc2n1C1CCc2cc(Br)cnc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 13.8 %

Procedure:
To a solution of NaH, 60% in oil, (163 mg) in 3 mL of 1,4-dioxane was added 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (1.1 gm) at room temperature and stirred for 30 minutes. Then 3-bromo-7-chloro-6,7-dihydro-5H-[1]pyrindine (500 mg, 2.15 mM) in 2 mL of 1,4-dioxane and anhydrous NaBr (442 mg) were added to the solution and the reaction was heated to 100° C. for 24 hours. The reaction was then cooled to room temperature, concentrated to dryness, and extracted into ethyl acetate from water. The organic layers were dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel to yield 110 mg of product.
Reaction SMILES: [Cl:1][C:2]([Cl:24])([Cl:23])[CH2:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:24][C:2]([Cl:1])([Cl:23])[CH2:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:34](=[O:35])[CH2:33][C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:37])([F:25])[F:38])=[CH:32][CH:31]=2)=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: O=C(OCC(Cl)(Cl)Cl)c1ccccc1CSc1ccc(CO)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1ccc(C(F)(F)F)cc1)OCc1ccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.4 %

Procedure:
2-(4-Hydroxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (70 mg, 0.173 mmol) was added to a stirred mixture of (4-trifluoromethyl-phenyl) acetic acid (39 mg, 0.190 mmol), EDCxHCl (50 mg, 0.259 mmol), DMAP (2.1 mg, 0.017 mmol) and DCM (3 mL). The reaction mixture was stirred at rt overnight, according to LC-MS analysis the reaction was uncomplete. Additional EDCxHCl (50 mg, 0.259 mmol), DMAP (2.1 mg, 0.017 mmol) and 2-(4-hydroxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (70 mg, 0.173 mmol) were added and the mixture was stirred for 3 h. More DCM was added and the mixture was washed with 0.25M HCl, the organic portion was dried through a phase separator and concentrated to give the titled compound (112 mg, 100%); Mass spectrum: M−H+ 590.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].Cl[C:14](=[CH2:17])[C:15]#[N:16]>CN(C)C=O>[C:15]([C:14]1[N:7]=[N:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])[CH:17]=1)#[N:16]
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Reactant: C=C(Cl)C#N
Solvent: CN(C)C=O
Product: N#Cc1cn(Cc2c(F)cccc2F)nn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile (26.6 g) and N,N-dimethylformamide (125 ml) is stirred at about 80° C. for 24 hours. Unreacted 2-chloro-acrylonitrile and 2,6-difluorobenzyl azide as well as N,N-dimethylformamide are distilled off (distillate 100 ml) by raising the external temperature to about 130° C. and gradually evacuating to about 100 mbar. After cooling to 100° C., water (100 ml) is allowed to run in. The crystallization of the product is initiated by seeding the brown emulsion. The mixture is cooled to about 20° C. and the suspension is stirred at about 20° C. for 30 minutes. The product is isolated by filtration and washed with water (100 ml). The product is dried in vacuo at about 60° C. Yield: 34.40 g=78.1% (beige crystals).