Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[N:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][CH:21]=2)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([C:24]1[N:25]=[C:20]([C:2]2[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=2)[CH:21]=[CH:22][CH:23]=1)#[N:27]
Reactant: CC1(C)OB(c2cccc(C#N)n2)OC1(C)C
Reactant: COC(=O)c1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cccc(C#N)n2)nn1
Temperature: 85 °C
Yield: 54.8 %

Procedure:
Methyl 6-chloropyridazine-3-carboxylate (S49, 34 mg, 0.19 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (45 mg, 0.19 mmol), K2CO3 (51 mg, 0.39 mmol), and (Ph3P)4Pd (34 mg, 0.029 mmol) were slurried in DMF (0.3 M). The reaction vessel was evacuated and refilled with argon three times. The mixture was warmed at 85° C. for 16 h. The reaction mixture was cooled and diluted with EtOAc, washed with 9:1 NH4OH:saturated aqueous NH4Cl and saturated aqueous NaCl, and then dried over Na2SO4 Evaporation yielded the crude product that was purified by flash chromatography (SiO2, 1.5×14 cm, 20-100% EtOAc-hexanes) to afford the title compound (25 mg, 53%) as a white solid: 1H NMR (CDCl3, 600 MHz) δ 9.03 (d, 1H, J=8.1 Hz), 8.75 (d, 1H, J=8.7 Hz), 8.36 (d, 1H, J=8.7 Hz), 8.09 (t, 1H, J=7.9 Hz), 7.84 (d, 1H, J=7.6 Hz), 4.12 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 164.4, 158.2, 154.4, 151.7, 138.7, 133.9, 129.8, 128.7, 125.5, 125.4, 116.9, 53.6; HRMS-ESI-TOF m/z 241.0721 ([M+H]+, C12H8N4O2 requires 241.0720).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29][N:9]([CH2:8][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: Cc1cccnc1CNCc1ncccc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)Cc1ncccc1Cl

Procedure:
Using General Procedure B: Reaction of C-(3-methyl-pyridin-2-yl)-methylamine and 3-chloro-pyridine-2-carboxaldehyde with NaBH(OAc)3 in CH2Cl2 gave (3-chloro-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amine as a yellow oil. Using General Procedure A: Reaction of (3-chloro-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amine, 2-bromomethyl-5-cyano-benzoic acid methyl ester, and DIPEA in CH3CN gave 2-{[(3-chloro-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester as a colorless oil. 1H NMR (CDCl3) δ 2.12 (s, 3H), 3.85 (s, 3H), 3.90 (s, 2H), 3.97 (s, 2H), 4.22 (s, 2H), 7.03 (dd, 1H, J=7.8, 4.8 Hz), 7.13 (dd, 1H, J=7.8, 4.8 Hz), 7.32 (d, 1H, J=6.9 Hz), 7.52-7.63 (m, 2H), 7.71 (d, 1H, J=8.1 Hz), 7.94 (d, 1H, J=1.5 Hz), 8.30 (d, 1H, J=4.5 Hz), 8.42 (dd, 1H, J=4.8, 1.5 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[F:13][CH:14]([F:17])[CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>O>[F:13][CH:14]([F:17])[CH2:15][O:16][C:2]1[N:3]=[C:4]([CH3:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: OCC(F)F
Reactant: COC(=O)c1ncc(Cl)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1ncc(OCC(F)F)nc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.1 %

Procedure:
To a mixture of methyl 5-chloro-3-methylpyrazine-2-carboxylate (255 mg, 1.367 mmol) in 2,2-difluoroethanol (0.52 mL, 8.20 mmol) was added potassium carbonate (227 mg, 1.640 mmol). The reaction was stirred at ambient temperature for 1.5 hrs. The reaction was treated with water and extracted with ethyl acetate. The organic portion was dried over Na2SO4, filtered, concentrated and purified by column chromatography, eluting with 0-2% MeOH/DCM to give the title compound (63.8 mg, 0.275 mmol, 20.1%). MS m/z=233.1 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:14][C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[CH:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[CH2:7]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[CH:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#CCCCCC(=O)NCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCCCCCNCc1ccccc1
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
Lithium aluminium hydride (1 m in THF, 10 ml, 10 mmol) was added to a solution of the amide from Step 1 (1.0 g, 4.6 mmol) in THF (20 ml) and the mixture was heated at reflux for 16 hours. The reaction was cooled in ice and treated successively with water (0.4 ml), sodium hydroxide (0.4 ml) and water (1.2 ml) allowing 10 minutes between additions. The mixture was filtered through a bed of Celite® and washed through with THF. The filtrate was evaporated in vacuo to provide 7-(N-benzylamino)hept-1-yne as a yellow oil (924 mg, 99%). (ES+) 202 ([MH]+).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH:13]=[CH:14][N:15]=[CH:16][C:10]3=[C:9]([C:17]([OH:19])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.[N:27]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1([C@@H](N)CC)C=CC=CC=1.[OH-].[Na+]>CC(N(C)C)=O.ClC(Cl)C.C(N(CC)CC)C>[C:1]1([C:7]2[N:12]=[C:11]3[CH:13]=[CH:14][N:15]=[CH:16][C:10]3=[C:9]([C:17]([NH2:27])=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cc(-c2ccccc2)nc2ccncc12
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CC[C@H](N)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: NC(=O)c1cc(-c2ccccc2)nc2ccncc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 250 mg of 2-phenylpyridino[4,3-b]pyridin-4-yl carboxylic acid dissolved in 5 mL of dimethylacetamide and 200 uL of triethylamine is added 500 mg of BOP in 5 mL of dichloroethane followed by 150 mg of (S)-1-phenylpropylamine. The reaction mixture is stirred for 16 hours at room temperature. The reaction mixture is poured onto 50 mL of 1N NaOH and the product is extracted with 25 mL of ethyl acetate. After drying over magnesium sulfate the solvent is removed in vacuo to afford N—[(S)-1-phenyl-1-propyl)]-(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide as a solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4](Cl)=[C:5]2[C:9](=[O:10])[CH2:8][CH2:7][C:6]=12.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:12]1[CH:17]=[CH:16][C:15]([C:2]2[S:3][C:4]([C:15]3[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=3)=[C:5]3[C:9](=[O:10])[CH2:8][CH2:7][C:6]=23)=[CH:14][CH:13]=1
Reactant: O=C1CCc2c(Cl)sc(Cl)c21
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: O=C1CCc2c(-c3ccncc3)sc(-c3ccncc3)c21
Yield: 49.6 %

Procedure:
To a stirred solution of 1,3-dichloro-5,6-dihydro-4H-cyclopenta(c)thiophen-4-one (923 mg, 4.45 mmol) in dimethoxyethane (23 mL) was added 4-pyridineboronic acid (1.3 g, 10.6 mmol), saturated aqueous NaHCO3 solution (7.5 mL), and bis(triphenylphosphine)palladium chloride (350 mg, 0.49 mmol) under nitrogen. The mixture was heated at reflux temperature for 36 hours. The reaction mixture wvas filtered through celite and the filtrate was extracted with ethyl acetate (100 mL×5). The combined organic layer was washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo. Chromatographic purification eluting with dichloromethane/methanol (25:1) and the subsequent recrystallization from ethyl acetate/hexane gave the title compound (645 mg, 50% yield) as yellow solids.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:30][C:31]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=3)=[O:32])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc4ccccc4c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.5 g), 2-bromo-1-(2-naphthyl)ethanone (1.16 g) and N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.19 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.84 g, 39%).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[F:34])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CN(C=O)C>[F:34][C:25]1[CH:26]=[C:27]([C:30]([F:32])([F:33])[F:31])[CH:28]=[CH:29][C:24]=1[CH:11]([C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[CH2:10][CH2:9][C:1]#[N:2]
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(C(F)(F)F)cc3F)c[nH]c12
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3F)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
726 mg (11.1 mmol) of potassium cyanide were added to 2.65 g (5.57 mmol) of the compound from Example 63A in 128 ml of DMF. The mixture was stirred at 80° C. for 2 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 1.46 g of the title compound were obtained with a purity of 85% (55% of theory).
Reaction SMILES: [CH3:1][N:2]1[C:11]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:19].C1C(=O)N([Br:27])C(=O)C1>C(Cl)Cl>[Br:27][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:19])[N:2]([CH3:1])[C:11]2([CH3:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1C(=O)Nc2ccccc2C1(C)c1ccccc1
Solvent: ClCCl
Product: CN1C(=O)Nc2ccc(Br)cc2C1(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,4-Dimethyl-4-phenyl-3,4-dihydro-1H-quinazolin-2-one (0.4 g, 1.59 mmol) in DCM (5 mL) is added NBS (0.28 g, 1.59 mmol). After the addition the mixture is stirred at room temperature overnight. The mixture is diluted with DCM, washed with H2O, dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by chromatography on silica gel to give product.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:10]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:8]([C:7]1[C:2]([C:17]2[CH:18]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=[CH:15][CH:16]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1cccnc1Cl
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=Cc1cccnc1-c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 93.7 %

Procedure:
To a suspension of 2-chloro-3-formylpyridine (0.708 g), 3-nitrophenylboronic acid (1.09 g) and tetrakis(triphenylphosphine)-palladium (289 mg) in 1,2-dimethoxyethane (20 ml) was added 2M aqueous solution of sodium carbonate (6.5 ml). The mixture was stirred at 80° C. for 14 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, h-hexane:ethyl acetate=1:1) to give 3-(3-formylpyrdin-2-yl)nitrobenzene (1.07 g).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][C:20]1[C:25](=[O:26])[N:24]2[CH2:27][CH2:28][CH2:29][CH:30]([OH:31])[C:23]2=[N:22][C:21]=1[CH3:32].C(N(C(C)C)CC)(C)C.[BH4-].[Na+]>CO.ClCCl>[CH3:32][C:21]1[N:22]=[C:23]2[N:24]([CH2:27][CH2:28][CH2:29][CH:30]2[OH:31])[C:25](=[O:26])[C:20]=1[CH2:19][CH2:18][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O
Temperature: 67.5 °C
Reaction time: 24 h

Procedure:
To the solution of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (formula-8) (10.0 grams) in methanol (50 ml), 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (formula-7) (11 grams) and diisopropyl ethyl amine (9 grams) were added. The reaction mixture heated to 65-70° C. and stirred for 24 hrs at the same temperature. The reaction mixture was cooled. Dichloromethane (100 ml) and sodium borohydride (0.086 grams) were added to it and stirred for 60 minutes at the same temperature. The solvent was distilled off under reduced temperature. Methanol was added to the residue and heated to reflux for 30 min. The reaction mixture was cooled to 20° C. and stirred for 1 hour. Filtered the solid precipitated. Washed the solid with chilled methanol and dried the compound.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[Br:12]Br>C(=S)=S>[Br:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[O:1][C:2](=[O:11])[CH2:3][CH2:4]2
Reactant: BrBr
Reactant: O=C1CCc2ccccc2O1
Solvent: S=C=S
Product: O=C1CCc2cc(Br)ccc2O1
Reaction time: 48 h
Yield: 85.3 %

Procedure:
To a solution of 74.08 g (0.50 mole) 2-chromanone in 150 ml carbon disulfide at 0° C. was added dropwise over 15 minutes, 79.91 g (0.50 mole) bromine. Stirring was continued at 0° C. for ten minutes and at room temperature for 2 days. The resulting mixture was filtered, the crystals air dried to afford 96.8 g (85%) of colorless material, m.p. 103°-105° C. (2 crops).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:19]2[O:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(OCC)(=O)C.[ClH:33]>C(OCC)(=O)C>[ClH:33].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:19]2[O:18][CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccccc1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A mixture of tert-butyl 9-(2-methoxyphenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (180 mg, 0.506 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (134 mg, 90.5%) as a solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:7][CH2:8][C:9]([F:12])([F:11])[F:10])[C:4]([NH2:6])=[O:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C1COCC1.C(N(CC)CC)C>O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:2][C@H:3]([CH2:7][CH2:8][C:9]([F:10])([F:11])[F:12])[C:4]([NH2:6])=[O:5])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NC(=O)[C@H](N)CCC(F)(F)F
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)[C@@H](CCC(F)(F)F)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a suitable dry vessel was added (R)-2-amino-5,5,5-trifluoropentanamide hydrochloride (199.52 g 0.966 mol, 1.0 equiv) followed by 4-chlorobenzenesulfonyl chloride (215.22 g 0.989 mol, 1.02 equiv, 97% w/w %) and 1.6 L of THF at room temperature. Triethylamine (206.5 g, 2.04 mol, 2.1 equiv.) was added over 20 min, maintaining the pot temperature at 15-25° C., and the resulting white slurry was stirred at 15-25° C. for 30 min. Water (1.4 L, 7 vol) of was added to the reaction mixture at 20-25° C. and then THF (1.4 L, 7 vol) was removed by distillation under vacuum (the pot temperature was maintained at 40-60° C. under 250-400 mmHg during distillation process). When the distillation process was complete, 1.4 L (7 vol) of water was added over 30 min while maintaining the pot temperature at 50-60° C., and the resulting slurry was stirred at 50-60° C. for 30 min and then cooled to 10° C. The slurry was agitated for not less than 1 hour, and the product was filtered. The filter cake was washed with water (600 mL each wash) until the pH of the cake wash measured ≧5. The cake was dried under vacuum at not more than 70° C. (jacket temp.) until the loss on drying is <0.5 w/w %, giving the title compound as a white solid (300 g, 91% yield.) 1H NMR (DMSO-d6) (400 MHz) δ 160-1.90 (two m, 1H each of CH2), 2.10-2.35 (m, 2H of CH2—CF3), 3.85-3.88 (m, 1H, —(CONH2)CH(NH), 7.13 & 7.37 (br s, 1H, each of CONH2), 7.61 (m, 2H, Ar—Ha), 7.64 (m, 2H, Ar—Hb), 8.18 (d, 1H, J=8.0 Hz, NH—SO2). 13C NMR (DMSO-d6) (100.0 MHz) δ 171.75, 140.27, 137.77, 131.71, 129.56, 128.95, 126.22, 55.12, 30.1, 29.82, 29.53, 29.25, 25.82, 25.79.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH:8]([N:10]2[C:23]3[CH:22]=[C:21]([C:24](Cl)=[O:25])[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:27]1([CH2:30][NH2:31])[CH2:29][CH2:28]1>ClCCl>[CH:27]1([CH2:30][NH:31][C:24]([C:21]2[CH:20]=[CH:19][C:18]3[S:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH:8]([CH3:9])[CH2:7][N:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)[C:23]=3[CH:22]=2)=[O:25])[CH2:29][CH2:28]1
Reactant: NCC1CC1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)Cl)cc21
Agent: Cl
Solvent: ClCCl
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)NCC3CC3)cc21
Yield: 86.1 %

Procedure:
By working in a manner similar to that described below in Example 103, but starting with 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonyl chloride hydrochloride (3.5 g) in dichloromethane (100 cc) and with cyclopropylmethylamine (3.8 g), N-(cyclopropylmethyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (3 g) is obtained in the form of a cream-coloured product of meringue-like consistency, which is dissolved in acetonitrile (20 cc). A 2.4N solution (8 cc) of hydrochloric acid in ethyl ether is then added. The crystals are drained and dried under reduced pressure (5 mm Hg; 0.67 kPa) at 40° C. N-(Cyclopropylmethyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide hydrochloride (2.6 g) is obtained in the form of white crystals, m.p. 220° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1.BrC1C=CC(C2N([C:39]3C=C[C:42]([S:45](N)(=O)=O)=[N:43][CH:44]=3)N=C(C(F)(F)F)C=2Cl)=CC=1>>[S:45]1[CH:39]=[C:44]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:12]([C:13]4[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=4)[N:11]=[C:10]([C:23]([F:24])([F:25])[F:26])[CH:9]=3)=[CH:4][CH:3]=2)[N:43]=[CH:42]1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cn1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Br)cc2)cn1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3cscn3)cc2)cn1

Procedure:
The title compound was prepared according to the procedure of step 3 in the Example 4 using 5-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide (Example 4, step 1), instead of 5-[5-(4-bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[CH3:27][N:28]([CH2:30][C:31]#[CH:32])[CH3:29]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:32]#[C:31][CH2:30][N:28]([CH3:29])[CH3:27])=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: C#CCN(C)C
Product: CN(C)CC#Cc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following Examples 43 and 60, Sonagoshira coupling of 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and N,N-dimethylpropargyl amine gave 125.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[S:6]([O-:10])([O-:9])(=[O:8])=[O:7].[Ca+2:11]>>[S:6]([O-:10])([O-:9])(=[O:8])=[O:7].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:11].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:11].[Ca+2:11]
Reactant: O=P(O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Product: O=P([O-])([O-])[O-]

Procedure:
In one embodiment, the impure aqueous phosphoric acid is a component of a solid calcium sulphate-containing slurry produced by the action of sulphate ion on a solution of a calcium phosphate-containing mineral in aqueous phosphoric acid. In another embodiment, said impure aqueous phosphoric acid can be the product of separation of solid calcium sulphate from a slurry comprising impure aqueous phosphoric acid and solid calcium sulphate.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][C:13]([C:16]([F:28])([F:27])[O:17][C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=3)=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>C1(C)C=CC=CC=1.C(O)C.[C].[Pd]>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]([F:27])([F:28])[O:17][C:18]3[CH:19]=[C:20]([F:26])[C:21]([F:25])=[C:22]([F:24])[CH:23]=3)[CH2:14][CH2:15]2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C2CC=C(C(F)(F)Oc3cc(F)c(F)c(F)c3)CC2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(F)(F)Oc3cc(F)c(F)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a nitrogen-purged 1-L stainless steel autoclave, 7.3 g (18.1 mmol) of 1-(4-(trans-4-propylcyclohexyl)cyclohexene-1-yl-difluoromethoxy)-3,4,5-trifluorobenzene obtained in the second step was dissolved in 250 ml of a mixed solution of equal amount of toluene/ethanol. 0.6 g of 5% palladium carbon catalyst was added thereto, and the mixture was stirred at room temperature under a hydrogen pressure of 0.8 MPa for 5 hours. The catalyst was separated from the reaction mixture by filtration, and then the solvent was distilled off under reduced pressure. The concentrated residue was purified by means of a silica gel column chromatography with heptane as a developing solvent and further recrystallized from a mixed solution of equal amount of heptane/ethanol to obtain 5.1 g of 1-(trans-4-(trans-4-propylcyclohexyl)-cyclohexyldifluoromethoxy)-3,4,5-trifluorobenzene as colorless crystals.