Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:18]1([NH:17][CH:6]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(OS(C)(=O)=O)c1cccs1
Reactant: Nc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(Nc1ccccc1)c1cccs1
Temperature: 100 °C
Yield: 76.7 %

Procedure:
Ethyl 2-(methylsulfonyloxy)-2-(thiophen-2-yl)acetate (I87) (5.7 g, 21.6 mmol), aniline (2.16 mL, 23.7 mmol) and DIPEA (4.52 mL, 25.9 mmol) are dissolved in acetonitrile (20 mL) to give a yellow solution which is heated under microwave irradiation into a sealed vial at 100° C. for 15 minutes. Conversion complete by UPLC/MS-UV. Solvent is evaporated and the residue is dissolved in DCM and washed with water and brine, dried (Na2SO4), filtered and evaporated to dryness. The resulting crude is purified by flash chromatography (Petroleum ether/EtOAc=85/15) to get desired compound as a yellow solid (4.33 g, 77% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])[C:12]=2[CH3:27])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1>CN(C=O)C>[F:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][O:1][C:2]2[CH:3]=[C:4]([NH:8][C:9]([C:11]3[CH:15]=[C:14]([CH3:16])[N:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]([F:26])([F:24])[F:25])[C:12]=3[CH3:27])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[CH:37][CH:38]=1
Reactant: Cc1cc(C(=O)Nc2cccc(O)c2)c(C)n1-c1ccccc1C(F)(F)F
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(OCc3ccc(F)cc3)c2)c(C)n1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
Into an oven-dried 1 dram vial was added 2,5-dimethyl-1-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid (3-hydroxy-phenyl)-amide (50 mg, 133 μmol), K2CO3 (22 mg, 160 μmol), 1-bromomethyl-4-fluoro-benzene (28 mg, 146 μmol) and 0.5 mL DMF. The vial was sealed and stirred 1 h at room temperature. The crude material was purified by reverse-phase chromatography (C18 column), eluting with 0.05% TFA in MeCN/H2O (30:70 to 90:10) to yield the title compound (19 mg, 30%) as an off-white solid. 1H-NMR (DMSO-d6): δ 9.43 (1H, s), 8.00 (1H, d, J=7.8), 7.90 (1H, t, J=7.8), 7.80 (1H, t, J=7.3), 7.58 (1H, m), 7.50 (3H, m), 7.35 (1H, d, J=8.6), 7.22 (3H, m), 6.69 (1H, d, J=8.3), 6.63 (1H, s), 5.07 (2H, s), 2.14 (3H, s), 1.88 (3H, s); MS (ESI): 483 (MH+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([N:13](C)[C:14](=O)OC(C)(C)C)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[ClH:24].CC(O)C>>[ClH:24].[CH3:14][NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:22])[F:23])[CH:4]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CC(C)O
Product: CNc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To the compound (12.4 g) obtained in step 2 was added 2N hydrogen chloride/2-propanol (100 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (9.36 g, 93%) as a white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[NH:32]1[CH:36]=[N:35][CH:34]=[N:33]1.[H-].[Na+]>CN1CCCC1=O>[CH3:21][C:5]1[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[N:7][C:2]([N:32]2[CH:36]=[N:35][CH:34]=[N:33]2)=[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:4]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-n2cncn2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 20, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with 1H-[1,2,4]triazole and sodium hydride in 1-methyl-pyrrolidin-2-one at reflux to give the title compound as colorless solid. MS: 485.3 (MH+).
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=O)[C:7]2=[O:15].Cl.[NH2:17][NH:18][C:19]([NH2:21])=[O:20]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=[N:17][NH:18][C:19]([NH2:21])=[O:20])[C:7]2=[O:15]
Reactant: NNC(N)=O
Reactant: COc1ccc2c(=O)c(=O)c(=O)c2c1
Agent: Cl
Solvent: O
Product: COc1ccc2c(=O)c(=NNC(N)=O)c(=O)c2c1

Procedure:
5-methoxyindan-1,2,3-trione, monohydrate, semicarbazide hydrochloride
Reaction SMILES: [Cl-].BrC1C(Br)=C(C)SC=1C[P+:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl:30][CH2:31][C:32]1[S:33][C:34](C)=[C:35]([Br:38])[C:36]=1[Br:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl-:30].[Br:38][C:35]1[C:36]([Br:37])=[C:32]([CH3:31])[S:33][C:34]=1[P+:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1sc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Br)c1Br
Reactant: Cc1sc(CCl)c(Br)c1Br
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1sc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Br)c1Br

Procedure:
(3,4-Dibromo-5-methyl-2-thenyl)triphenyl phosphonium chloride can be prepared in a manner analogous to that described in Example 13 by reaction of 2-chloromethyl-3,4-dibromo-5-methyl-thiophene with triphenyl phosphine, m.p. 215°-216° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[CH3:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Br)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)C1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(2-Bromo-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.30 mmol) was dissolved in dry N,N-dimethylformamide (5.0 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 62.6 mg, 1.56 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for one hour. To the reaction mixture was then added at 0° C. methyl iodide (0.241 g, 1.70 mmol). The reaction mixture was stirred at 0° C. for one hour, then at room temperature under nitrogen atmosphere for 3 hours. The reaction mixture was then added into an excess of water-ice and a gum formed. The gum was filtered by suction, washed with water and dried to yield a crude solid. The crude solid was purified via flash chromatography (25% ethyl acetate/hexanes) to yield the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)=O.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1
Reactant: COc1ccc(C(=O)c2ccc3ccccc3c2)c(Br)c1
Agent: CC[SiH](CC)CC
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cc2ccc3ccccc3c2)c(Br)c1
Temperature: 50 °C
Yield: 82 %

Procedure:
To the methanone of Step 1 (14.0 g) and triethylsilane (15 mL) in 15 mL of CHCl3 was added TFA and was heated to 50° C. overnight. The solution was cooled and quenched with NaOH (2N) to provide the title compound in 82% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.Br.Br.Br.[CH2:12]([C:14]1[C:15]([C:22]2[CH:30]=[C:29]3[C:25]([C:26]([C:31]4[NH:40][C:34]5[CH2:35][CH2:36][NH:37][CH2:38][CH2:39][C:33]=5[N:32]=4)=[N:27][NH:28]3)=[CH:24][CH:23]=2)=[CH:16][C:17]([F:21])=[C:18]([OH:20])[CH:19]=1)[CH3:13]>>[CH2:12]([C:14]1[CH:19]=[C:18]([OH:20])[C:17]([F:21])=[CH:16][C:15]=1[C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:31]3[NH:40][C:34]4[CH2:35][CH2:36][N:37]([C:6]([C:3]5[CH:4]=[CH:5][S:1][N:2]=5)=[O:8])[CH2:38][CH2:39][C:33]=4[N:32]=3)=[N:27][NH:28]2)=[CH:24][CH:23]=1)[CH3:13]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNCC4)n[nH]c2c1
Reactant: O=C(O)c1ccsn1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3ccsn3)CC4)n[nH]c2c1
Yield: 25.6 %

Procedure:
The title compound was prepared from isothiazole-3-carboxylic acid (11 mg, 85 μmol) and 5-ethyl-2-fluoro-4-[3-(1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 32, 50 mg, 80 μmol) using the method of Example 8. The crude material was purified by HPLC Method B to afford 10.3 mg of the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([CH:17]=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.CCCCCC.[C:25]([O:28][CH2:29][CH3:30])(=[O:27])[CH3:26]>O1CCCC1>[CH2:29]([O:28][C:25](=[O:27])[CH:26]=[CH:17][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:30]
Reactant: O=Cc1cccc2ccccc12
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C=Cc1cccc2ccccc12
Reaction time: 8 h
Yield: 90 %

Procedure:
22.4 g(0.10 mol) of triethylphosphonoacetate was dissolved in 500 ml of tetrahydrofuran and 12.4 g(1.1 mol) of potassium t-butoxide was slowly added thereto. To this solution was slowly added 15.6 g(0.10 mol) of 1-naphthaldehyde dissolved in 20 ml of tetrahydrofuran, then the resulting solution was stirred for 8 hours. The organic solvent was eliminated by distillation under reduced pressure, and the residue was dissolved in ethyl acetate, washed twice with water, dried over magnesium sulfate and concentrated. The concentrate was subjected to silica gel column chromatography(eluent: n-hexane/ethyl acetate=95/5, v/v) to obtain 20.3 g(0.090 mol, Yield 90%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[C:8]([F:15])[C:9]([O:13]C)=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:16]2[S:17][C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=2)[CH:4]=1)#[N:2].B(Br)(Br)Br.Cl>ClCCl>[C:1]([C:3]1[C:12]2[C:7](=[C:8]([F:15])[C:9]([OH:13])=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:16]2[S:17][C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=2)[CH:4]=1)#[N:2]
Reactant: COc1ccc2c(C#N)cc(-c3nc(C)c(C(=O)O)s3)cc2c1F
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Cc1nc(-c2cc(C#N)c3ccc(O)c(F)c3c2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.5 %

Procedure:
To a suspension of 2-(4-cyano-8-fluoro-7-methoxynaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid (0.22 g) in dichloromethane (1 mL) was added boron tribromide (1 mol/L dichloromethane solution, 128 μL) under methanol-ice-cooling, and the mixture was stirred at room temperature for 30 minutes, followed by stirring with heating at 40° C. for 2.5 hours. After cooling to room temperature, to the mixture was added 1 mol/L hydrochloric acid. The precipitated crystal was collected by filtration, and dried under reduced pressure at 50° C. to give the title compound (0.018 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([O:17][CH:18]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)=[O:25])[CH2:19][CH2:20][C:21](O)=[O:22])=[C:11]2[CH:10]=[N:9]1.CN.[CH3:36][N:37](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([O:17][CH:18]([CH2:19][CH2:20][C:21]([NH:37][CH3:36])=[O:22])[C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)=[O:25])=[C:11]2[CH:10]=[N:9]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccc(NC(=O)C(CCC(=O)O)Oc2ncnc3c2cnn3-c2ccccc2Cl)nc1
Agent: CN
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)CCC(Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1ccc(C)cn1
Reaction time: 0.75 h
Yield: 56.8 %

Procedure:
A solution of 4-{[1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy}-5-[(5-methylpyridin-2-yl)amino]-5-oxopentanoic acid (5.0 mg, 0.011 mmol), methylamine (0.021 ml (2M in THF), 0.043 mmol) and TBTU (7.0 mg, 0.021 mmol) in THF (1 mL) was stirred at ambient temperature for 5 hrs. Water (1 mL) was added and the reaction mixture was purified by preparative HPLC: Mobile phase A: 100% ACN, Mobile phase B: 5% ACN+95% 0.1M NH4OAc in water; Gradient: 0% A to 50% A over 45 min; Flow: 25 ml/min; UV: 235 nm, to give the title compound (3.0 mg). 1H NMR (500 MHz, CDCl3) δ 8.88 (br s, 1H), 8.57 (s, 1H), 8.39 (s, 1H), 8.11 (m, 2H), 7.62 (m, 1H), 7.51 (m, 4H), 5.91 (m, 1H), 5.63 (br s, 1H), 2.82 (d, 3H), 2.51 (m, 4H), 2.30 (s, 3H), HRMS: calcd for (M+H+) C23H2335ClN7O3: 480.1551. Found: 480.1503.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]([CH3:7])[CH2:4][CH:3]([CH3:8])[CH2:2]1.C(N(CC)CC)C.[C:16]1([S:22]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC>[C:16]1([S:22][N:1]2[CH2:6][CH:5]([CH3:7])[CH2:4][CH:3]([CH3:8])[CH2:2]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1CNCC(C)C1
Reactant: ClSc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC1CC(C)CN(Sc2ccccc2)C1

Procedure:
In a flask, 3,5-lupetidine (22.9 parts), triethylamine (20.4 parts) and ether (200 parts) are charged, and phenylsulfenyl chloride (27.7 parts) is dropwise added thereto. The resultant mixture is stirred at 30°C for 6 hours. The reaction mixture is filtered to separate the precipitate and the filtrate is distilled to give N-phenylthio-3,5-lupetidine (36 parts by weight). B.P.; 134°C/4 mmHg. nD25 1.5511.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Br:10])=[C:6]([NH:11][CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[O:23][CH2:24][CH2:25][CH3:26])[C:5]([N+:27]([O-])=O)=[N:4]1)[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)(=O)C>C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Br:10])=[C:6]([NH:11][CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[O:23][CH2:24][CH2:25][CH3:26])[C:5]([NH2:27])=[N:4]1)[CH3:2]
Reactant: CCCOc1ccc2ccccc2c1CNc1c([N+](=O)[O-])nn(CC)c(=O)c1Br
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCOc1ccc2ccccc2c1CNc1c(N)nn(CC)c(=O)c1Br
Yield: 2 %

Procedure:
530 mg of 2-ethyl-4-bromo-5-(2-n-propoxy-1- naphthylmethylamino)-6-nitro-3(2H)pyridazinone (Compound No. 48) was dissolved in a mixture comprising 50 ml of ethanol and 25 ml of a 10 wt% sodium carbonate aqueous solution. Then, 1.0 g of sodium hydrosulfite was gradually added under stirring, and the mixture was then stirred at room temperature for 2.5 hours. Glacial acetic acid was added to neutralize the reaction solution. Then, the solvent was distilled off under reduced pressure. Water was poured to the residue thus obtained, and the mixture was extracted with chloroform. The extract was washed sequentially with water and with a saturated sodium chloride aqueous solution and then dried over sodium sulfate. Then, the solvent was distilled off to obtain a residual yellowish orange solid substance. This product was purified by silica gel column chromatography by using chloroform and a mixture of chloroform/methanol (volume ratio of 10/1) as developers to obtain 10 mg of colorless crystals. This product was found to show the same behavior on the silica gel thin layer chromatography as the substance obtained in the above method (i), and was identical with it also in NMR, MS and IR spectrum.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]1([C:60]([O:62][CH3:63])=[O:61])[CH2:59][CH2:58]1)#[CH:50].CCN(CC)CC>CN(C=O)C.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.[Cu]I>[CH3:63][O:62][C:60]([C:57]1([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=2[C:49]#[C:50][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]4)=[CH:15][CH:14]=3)[N:3]=2)[CH2:59][CH2:58]1)=[O:61]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)C1
Reactant: C#Cc1ccccc1C1(C(=O)OC)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccccc2C#Cc2nc(Nc3ccc(C4CN(C(=O)OC(C)(C)C)C4)cc3)ncc2C(F)(F)F)CC1
Temperature: 120 °C
Yield: 100 %

Procedure:
A solution of tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (K4) (260 mg, 0.606 mmol), PdCl2(PPh3)2 (21 mg, 0.030 mmol), PPh3 (16 mg, 0.061 mmol), CuI (12 mg, 0.061 mmol) and methyl 1-(2-ethynylphenyl)cyclopropanecarboxylate (K2) (146 mg, 0.728 mmol) in DMF (3.0 mL) was degassed with nitrogen for 10 minutes. Et3N (1.0 mL) was added and the resulting mixture heated under microwave irradiation at 120° C. for 20 minutes. The resulting mixture was adsorbed onto silica and purified by silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-25% EtOAc in petroleum benzine 40-60° C.) to give the title compound A7 as an orange oil (359 mg, >95%); 1H NMR (400 MHz, d6-DMSO) δ 10.45 (s, 1H), 8.82 (s, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.61 (dd, J=7.5, 1.0 Hz, 1H), 7.55-7.38 (m, 3H), 7.32 (d, J=8.6 Hz, 2H), 4.32-4.17 (m, 2H), 3.89-3.74 (m, 3H), 3.52 (s, 3H), 1.64 (q, J=4.0 Hz, 2H), 1.40 (s, 9H), 1.29 (q, J=4.2 Hz, 2H). LCMS-A: rt 6.550 min; m/z 593 [M+H]+.
Reaction SMILES: CC([O-])(C)C.[K+].F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[Cl:17][CH2:18][CH2:19][CH2:20][SH:21]>CS(C)=O.O>[Cl:17][CH2:18][CH2:19][CH2:20][S:21][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1
Reactant: SCCCCl
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(SCCCCl)cc1
Temperature: 10 °C
Yield: 33.4 %

Procedure:
To a cooled (10° C.), stirred suspension of KOtBu (8.9 g, 0.080 mol) in DMSO (40 mL) was added a solution of 4-fluoronitrobenzene (11.2 g, 0.080 mol) and 3-chloropropanethiol (8.8 g, 0.080 mol) in DMSO (40 mL) over 10 minutes. The mixture was stirred at room temperature for 3.5 hours, diluted with water (1000 ml), and extracted with ether. The extracts were washed with brine, dried (MgSO4), and concentrated. Purification by flash chromatography (10% EtOAc/hexane) gave 6.2 g (34%) of product as a yellow solid m.p. 45°-48° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([S:23]([CH3:22])(=[O:25])=[O:24])[CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CNC1CCN(C(=O)OC(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C1CCN(C(=O)OC(C)(C)C)C1)S(C)(=O)=O
Reaction time: 24 h

Procedure:
To a solution of 3-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g) in dichloromethane (10 ml) was added triethylamine (0.38 ml) followed by methanesulfonyl chloride (0.21 ml). After stirring for 24 hours the reaction mixture was diluted with dichloromethane, washed with sodium bicarbonate solution, dried (Mg2SO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 3-(methanesulfonyl-methyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.52 g). Treatment of this compound with HCl in dichloromethane/methanol yielded N-Methyl-N-pyrrolidin-3-yl-methanesulfonamide hydrochloride salt (0.41 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C:21](=[O:23])[CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@H:21]([OH:23])[CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1
Reaction time: 1 h

Procedure:
To a solution of 1-[(3R,4S)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethanone (260 mg, 0.78 mmol) in THF (10 mL) at 0° C. were added portion wise LiAlH4 (26 mg, 0.68 mmol). Stirring was continued for one hour, and the reaction mixture was carefully quenched by addition of aq. NH4Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO2, EtOAc/H, 1:1) to yield (R)-1-[(3R,4S)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol (X-B-9) 101 mg (38%) as a white solid ES-MS m/e: 334.2(M+H+) and (S)-1-[(3R,4S)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol (X-A-9) 80 mg (30%) as a white solid ES-MS m/e: 334.2 (M+H+).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16]O)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:25]>C(OCC)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][Br:25])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCCCc1cccc(Oc2ccccc2)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: BrCCCc1cccc(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 209.4 %

Procedure:
To a mixture of 21.0 grams (0.092 mole) of 3-(3-phenoxyphenyl)propanol and 1 mL of pyridine which had been cooled to 0° C. was added dropwise during a 20 minute period 8.27 grams (0.031 mole) of phosphorus tribromide. This mixture was stirred at 0° C. for 90 minutes and then at ambient temperature overnight. The reaction mixture was then diluted with 200 mL of diethyl ether, and the solution was washed successively twice with 50 mL of water, four times with 25 mL of a saturated, aqueous solution of sodium bicarbonate, once with 50 mL of water, and once with an aqueous solution of sodium chloride. After being dried over anhydrous sodium sulfate and filtered, the solvent was evaporated under reduced pressure, leaving 18.9 grams of 3-(3-phenoxyphenyl)propyl bromide as an oil. The nmr spectrum was consistent with the proposed structure.