Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][NH:25][C:26]1[C:27]([CH3:41])=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[N:28][C:27]([CH3:41])=[C:26]([NH:25][CH3:24])[CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CNc1cc(B2OC(C)(C)C(C)(C)O2)cnc1C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CNc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and methyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 163.1.1) to give the title compound as a white solid. (HPLC: tR 2.10 min (Method A); M+H=414 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.12-8.06 (m, 2H), 7.96-7.92 (m, 1H), 7.89-7.87 (m, 1H), 7.62-7.60 (m, 1H), 6.73-6.70 (m, 1H), 5.51 (q, br, 1H), 3.88 (s, 3H), 3.57 (s, 3H), 2.80 (d, 3H), 2.31 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: O.NN.[C:4]1([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)=O)=[CH:17][N:18]=3)[N:15]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[K+].C(O)COCCO>O>[C:4]1([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([CH2:19][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)=[CH:17][N:18]=3)[N:15]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1ccc2ncccc2c1)c1cnc2ccc(-c3ccccc3)nn12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: c1ccc(-c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1
Reaction time: 0.08 h

Procedure:
A 10-20 mL microwave vial was charged with hydrazine hydrate (0.0312 ml, 0.642 mmol), (6-phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.150 g, 0.428 mmol), KOH (0.0961 g, 1.71 mmol), and diethylene glycol (4.09 ml, 42.8 mmol), sealed, then placed in a Personal Chemistry microwave at 130° C. for 20 minutes after a 5 minute pre-stir. The mixture was diluted with water (75 mL), then extracted with DCM (2×75 mL). The combined organics were washed with brine (75 mL), then dried with MgSO4, filtered, and concentrated to give a brown solid, then purified by prep HPLC to give the product as the formic acid salt. MS (ESI pos. ion) m/z: 337 (MH+). Calc'd exact mass for C22H16N4: 336.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][CH3:12].[Mg].CN(C)[CH:16]=[O:17].[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:12][O:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH:16]=[O:17]
Reactant: CN(C)C=O
Reactant: COCCc1cccc(C)c1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COCCc1cccc(C)c1C=O
Temperature: 25 °C
Yield: 15 %

Procedure:
To a stirred solution of 2-(2-bromo-3-methylphenyl)ethyl methylether (1.5 g, 6.5 mmol) in anhydrous tetrahydrofuran (10 ml) was added magnesium (turnings) (0.16 g, 6.6 mmol). The mixture was refluxed in a nitrogen atmosphere until the reaction started and then stirred without heating for 15 min. The mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature and N,N-dimethylformamide (0.7 g) was added and the mixture was stirred for 30 min. A saturated ammonium chloride solution (10 ml) was added and the mixture was stirred for 1 h. at room temperature. Toluene (20 ml) was added and the organic layer was separated, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride as eluent to separate the lipophilic biproducts and methylene chloride/diethyl ether(7:3) as eluent to isolate (0.17 g, (15%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].CC(C)([O-])C.[K+].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18]Cl.O>C1COCC1>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COC(CCl)OC
Reactant: Fc1ccccc1S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(CSc1ccccc1F)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Fluorothiophenol (4.14 g, 32.6 mmol) was dissolved in anhydrous THF (100 mL). Potassium tert-butoxide (1.0 M in THF, 35.8 mL) was added and the suspension was stirred at room temperature for 15 minutes. 2-Chloroacetaldehyde dimethyl acetal was added and the mixture was stirred for 3 days. Water (100 mL) was added and the solution was extracted with diethyl ether (3×100 mL). The extracts were concentrated to a yellow oil and chromatographed (5 to 20% ethyl acetate in hexane) to yield 1-(2,2-dimethoxy-ethylsulfanyl)-2-fluoro-benzene (6.42 g) as a colorless oil. Chlorobenzene (25 mL) was heated to reflux and polyphosphoric acid (1 mL) was added. The 1-(2,2-dimethoxy-ethylsulfanyl)-2-fluoro-benzene was then added slowly turning the solution dark. After 3 hours of heating, the reaction was cooled to room temperature and diluted with water (50 mL). The solution was extracted with benzene (2×50 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 7-fluorobenzothiophenyl (0.77 g). The 7-fluorobenzothiophenyl (0.77 g, 5.1 mmol) and dichloromethyl methyl ether (0.872 g, 7.6 mmol) were dissolved in anhydrous DCM (25 mL). Titanium tetrachloride (1.0 M in DCM, 7.6 mL, 7.6 mmol) was added, turning the solution dark. After 30 minutes at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×50 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 7-fluorobenzothiophene-3-carboxaldehyde (0.642 g). The 7-fluorobenzothiophene-3-carboxaldehyde (0.642 g, 3.77 mmol) and sulfamide (1.7 g, 18 mmol) were combined in anhydrous ethanol (20 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.148 g, 3.92 mmol) was added. After two hours, water (25 ml) was added and the solution was extracted with chloroform (3×25 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to yield the title compound as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH:29]4[CH2:31][CH2:30]4)=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[N:12][CH:13]=1>>[CH:29]1([C:25]2[CH:26]=[C:27]([CH3:28])[C:22]([N:19]3[CH2:20][CH2:21][N:16]([C:14]([C:11]4[N:12]=[CH:13][C:8]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[CH:9][CH:10]=4)=[O:15])[CH2:17][CH2:18]3)=[N:23][CH:24]=2)[CH2:30][CH2:31]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cn2)CC1
Reactant: O=C1CCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cn2)CC1
Yield: 59.4 %

Procedure:
Using pyrrolidin-2-one (72 mg) and (5-bromopyridin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (310 mg) described in Preparation Example 135 and by the reaction and treatment in the same manner as in Example 1, the title compound (186 mg) was obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:8]=2/[CH:9]=[C:10]2/[C:11](=[O:16])[NH:12][C:13](=[O:15])[S:14]/2)[CH2:3]1.[CH3:22][N:23]1[CH:27]=[CH:26][N:25]=[C:24]1[C:28](O)=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:8](/[CH:9]=[C:10]2/[C:11](=[O:16])[NH:12][C:13](=[O:15])[S:14]/2)[C:7]=1[N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:28]([C:24]2[N:23]([CH3:22])[CH:27]=[CH:26][N:25]=2)=[O:29])[CH2:3]1
Reactant: N[C@H]1CCN(c2c(Cl)cccc2/C=C2\SC(=O)NC2=O)C1
Reactant: Cn1ccnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ccnc1C(=O)N[C@H]1CCN(c2c(Cl)cccc2/C=C2\SC(=O)NC2=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.1 %

Procedure:
To a 50 mL vial charged with a magnetic stir bar was added (S,Z)-5-(2-(3-aminopyrrolidin-1-yl)-3-chlorobenzylidene)thiazolidine-2,4-dione (75 mg, 0.23 mmol) (Example 86), 1-methyl-1H-imidazole-2-carboxylic acid (87 mg, 0.69 mmol), HATU (220 mg, 0.58 mmol) and dichloromethane (5 mL). Hunig's base (0.202 mL, 1.16 mmol) was then added and the mixture was stirred at rt for 4 h. The reaction was then diluted with dichloromethane and washed with water. The mixture was separated with a phase separator tube and the organic phase was evaporated to dryness. The residue was purified by reverse phase chromatography to afford the title compound as a yellow solid (21 mg, 21%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (s, 1 H) 7.51 (dd, 1 H) 7.41 (dd, 1 H) 7.18-7.27 (m, 2 H) 7.01 (s, 1 H) 4.67-4.77 (m, 1 H) 4.00 (s, 3 H) 3.63-3.75 (m, 2 H) 3.47-3.54 (m, 1 H) 3.36-3.47 (m, 1 H) 2.39-2.51 (m, 1 H) 2.14 (dd, 1 H); m/z 432.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[Br:11]Br.O>C(O)(=O)C>[Br:11][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH3:1])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
To a solution of 4-hydroxyacetophenone (6.8 g, 0.05 mol, 1 eq) in 60% acetic acid (50 mL), was added a solution of bromine (2.6 mL, 0.05 mol, 1 eq) in 80% acetic acid (20 mL). After stirring at room temperature for 30 min, the reaction mixture was poured into 100 mL of cold water. The solid was filtered and the filtrate was further diluted with 500 mL of cold water. The white precipitate was collected by filtration, washed with water and dried under vacuum to afford 4.2 g (39%) of 1-(3-bromo-4-hydroxyphenyl)ethanone (15) as white solid. 1HNMR (CDCl3, 400 MHz): δ 8.15 (s, 1H), 7.86 (d, 1H), 7.18 (d, 1H), 5.96 (s, 1H), 2.56 (s, 3H). MS (ES-API): M+1=216.9. HPLC (Method B) tR=2.48 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH:3]([NH:16][CH2:17][C:18]1[C:23]([N+:24]([O-])=O)=[CH:22][N:21]=[C:20]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:19]=1)[C:4]([N:6]([CH3:15])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].C(O)C>[Pd].C(OCC)(=O)C>[NH2:24][C:23]1[C:18]([CH2:17][NH:16][CH:3]([CH:2]([CH3:34])[CH3:1])[C:4]([N:6]([CH3:15])[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])=[CH:19][C:20]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[N:21][CH:22]=1
Reactant: CC(C)C(NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C(=O)N(C)CCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)C(NCc1cc(Oc2ccccc2)ncc1N)C(=O)N(C)CCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of 3,N-dimethyl-2-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-N-phenethyl-butyramide (2.1 g, 1.38 mmol), 10% Pd on carbon (2 g), ethanol (75 mL) and ethyl acetate (75 mL) were shaken under a hydrogen atmosphere (50 psi). After 2 hours, the hydrogen was evacuated and the bottle was purged with nitrogen. The resulting mixture was filtered through glass fiber filter paper and the solvent evaporated under low pressure to yield a solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19](=[O:29])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[C:22]([F:28])[CH:21]=1.C[O-].[Na+].Cl>CO.O>[CH3:17][O:18][C:19](=[O:29])[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:15]/[C:14](=[O:16])[C:13]2[C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:22]([F:28])[CH:21]=1
Reactant: CC(=O)c1cccnc1Nc1ccccc1
Reactant: COC(=O)c1ccc(C=O)c(F)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(/C=C/C(=O)c2cccnc2Nc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.5 %

Procedure:
A mixture of 1-(2-phenylamino-pyridin-3-yl)-ethanone (700 mg, 3.3 mmol) in methanol (16.5 mL) at 25° C. was treated with 3-fluoro-4-formyl-benzoic acid methyl ester (601 mg, 3.3 mmol, calculated from 50% mixture) and sodium methoxide in methanol (4.37M, 1.51 mL, 6.6 mmol). The reaction was stirred at 25° C. for 48 h. At this time, the reaction was diluted with water (50 mL), neutralized with a 2N aqueous hydrochloric acid solution, and extracted with methylene chloride (3×75 mL). The combined organics were dried over sodium sulfate and filtered. Silica gel was added to the filtrate, concentrated in vacuo and dried under high vacuum. Flash Chromatography (40 g silica column, 1% methanol/methylene chloride) afforded 3-fluoro-4-[(E)-3-oxo-3-(2-phenylamino-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (1 g, 80.6%) as a red solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][C:17](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.NC1C=CC(C2CCC(C(OC)=O)C2)=CC=1>>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16]2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)C=C1CCCC(c2ccc(OCc3ccccc3)cc2)C1
Agent: COC(=O)C1CCC(c2ccc(N)cc2)C1
Product: CCOC(=O)CC1CCCC(c2ccc(O)cc2)C1

Procedure:
Ethyl {3-[4-(benzyloxy)phenyl]cyclohexylidene}acetate was reduced following the general procedure described for Intermediate 84, part (ii), to give the title compound; 1H NMR δ 1.12-1.19 (3H, m), 0.93-1.82 (8H, m), 2.18 (1H, d), 2.45 (1H, d), 2.65 (1H, m), 2.99 (1H, m), 4.04 (2H, q), 6.65-6.67 (2H, m), 7.00 (2H, t), 9.12 (1H, s); MS m/e (M−H)− 261.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]3[C:12](=[O:17])[C:13](I)=[CH:14][CH:15]=[C:10]3[N:9]2[S:26]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])(=[O:28])=[O:27])=[CH:4][CH:3]=1.[CH3:37][C:38]([CH3:43])=[CH:39]B(O)O>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]3[C:12](=[O:17])[C:13]([CH:37]=[C:38]([CH3:43])[CH3:39])=[CH:14][CH:15]=[C:10]3[N:9]2[S:26]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])(=[O:28])=[O:27])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(S(=O)(=O)N2c3ccc(I)c(=O)n3[C@H](c3ccc(Cl)cc3)[C@@H]2c2ccc(Cl)cc2)c1
Reactant: CC(C)=CB(O)O
Solvent: ClCCl
Solvent: CO
Product: CC(C)=Cc1ccc2n(c1=O)[C@H](c1ccc(Cl)cc1)[C@H](c1ccc(Cl)cc1)N2S(=O)(=O)c1cccc(C#N)c1

Procedure:
The titled compound was prepared according to general method D by reaction of rac-3-[cis-2,3-bis-(4-chloro-phenyl)-5-oxo-2,3-dihydro-6-iodo-5H-imidazo[1,2-a]pyridine-1-sulfonyl]-benzonitrile with 2,2-dimethylethenylboronic acid. The compound was isolated by FCC (2.5% MeOH/DCM). The expected product was characterized by 1H NMR
Reaction SMILES: [N:1]1([CH2:6][C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Ni].CO>[N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:21][CH:22]=3)=[O:16])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1ccc(C#CCN2CCCC2)cc1)c1ccc(OC2CCCCO2)cc1
Agent: [Ni]
Solvent: CO
Product: O=C(c1ccc(CCCN2CCCC2)cc1)c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
A flask was charged with (4-(3-(pyrrolidin-1-yl)prop-1-ynyl)phenyl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (391 mg, 1 mmol), Riney Ni (0.2 eq), and 20 mL of methanol. The mixture was stirred under hydrogen at room temperature and atmospheric pressure for 2 h. After complete conversion (TLC monitoring), the catalyst was filtered off through a pad of celite, and washed with EtOAc. The filtrate was concentrated under reduced pressure to give the product (375 mg, 95% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[CH:4]=[C:5]([C:7]#[N:8])[CH:6]=1.[I:21]N1C(=O)CCC1=O>C(#N)C.O>[NH2:1][C:2]1[N:3]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:17])[F:18])=[CH:11][C:10]=2[Cl:20])[CH:4]=[C:5]([C:7]#[N:8])[C:6]=1[I:21]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1
Solvent: CC#N
Solvent: O
Product: N#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-1-(2,6-dichloro4-trifluoromethylphenyl)4-cyanopyrrole (EP-372982 A2) in acetonitrile (20 ml) was added N-iodosuccinimide (703 mg). The reaction was stirred at room temperature for 30 minutes, diluted with water (100 ml) and extracted with ether (100 ml). The organic fraction was separated, dried over MgSO4, filtered and evaporated to dryness, the residue was purified by column chromatography (silica, 20 g) eluted with dichloromethane:hexane (7:3) to give the title compound as a yellow crystaline material, m.p. 130-132° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[CH:20]12[CH2:26][CH:23]([NH:24][CH2:25]1)[CH2:22][O:21]2.O>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:24]2[CH2:25][C@@H:20]3[CH2:26][C@H:23]2[CH2:22][O:21]3)[CH:7]=1
Reactant: C1OC2CNC1C2
Reactant: CSc1nc(Cl)cc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(Cl)cc(N2C[C@@H]3C[C@H]2CO3)n1
Temperature: 50 °C
Reaction time: 12 h
Yield: 92.4 %

Procedure:
The mixture of 4,6-dichloro-2-(methylthio)pyrimidine (450 mg, 2.31 mmol), DIEA (894 mg, 6.92 mmol) and 2-oxa-5-azabicyclo[2.2.1]heptane (328 mg, 2.42 mmol) in DMF (5 mL) was stirred at 50° C. for 12 h. Water (20 mL) was added to and extracted with ethyl acetate (2×20 mL). The organic layers were dried over Na2SO4, filtered and concentrated to give (1S,4S)-5-(6-chloro-2-(methylthio)pyrimidin-4-yl)-2-oxa-5-azabicyclo-[2.2.1]heptane (550 mg, 92.5% yield) as a white solid, which was used for next step without further purification LCMS (ESI): [MH]+=258.0.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH:9]([OH:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][CH:15]1CCCN(C)C1(C)C.ICC>CO>[CH2:14]([N:11]1[CH2:12][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C@H:9]([OH:13])[CH2:10]1)[CH3:15]
Reactant: OC1CNCC(c2ccccc2)C1
Reactant: CC1CCCN(C)C1(C)C
Solvent: CO
Solvent: CCI
Product: CCN1C[C@@H](O)C[C@@H](c2ccccc2)C1

Procedure:
5-Phenyl-3-piperidinol (5.2 g), tetramethylpiperidine (8.3 ml) and iodoethane (1.97 ml) was stirred at room temperature in methanol (100 ml) for 48 hours. The methanol was removed under reduced pressure and excess 2 M NaOH added. The oil was extracted with ether and washed with brine. After drying (MgSO4) the ether was removed and the product crystallised affording, after recrystallisation from cyclohexane, 3.2 g of pure title compound which could be converted to the hydrochloride salt m.p. 182°-4° C.
Reaction SMILES: [OH:1][C@H:2]([C:19]1[C:20]([CH3:29])=[C:21]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[O:23][CH2:22]2)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C@H:5]1[CH2:17]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[C:42]([O-:45])(=[S:44])[CH3:43].[K+]>C1COCC1.CN(C)C1C=CN=CC=1.CS(C)=O.C(OCC)(=O)C>[C:42]([S:44][CH2:17][C@H:5]1[N:4]([CH2:3][C@H:2]([OH:1])[C:19]2[C:20]([CH3:29])=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[O:23][CH2:22]3)[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:6]1)(=[O:45])[CH3:43]
Reactant: Cc1c([C@@H](O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc2c1COC2=O
Reactant: CC([O-])=S
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C[C@H](O)c1ccc2c(c1C)COC2=O
Reaction time: 2 h

Procedure:
To the solution of (S)-tert-butyl 4-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (817 mg, 2.01 mmol) in anhydrous THF (20 mL) under nitrogen atmosphere at 0° C. was added anhydrous triethylamine (0.560 mL, 4.02 mmol), followed by addition of methanesulfonyl chloride (0.234 mL, 3.01 mmol) and 4-dimethylaminopyridine (24.6 mg, 0.201 mmol). The ice bath removed and reaction mixture was stirred for 2 hours. Resulting mixture was then concentrated under reduced pressure. Resulting oil was redissolved in anhydrous DMSO (13 mL) and treated with potassium thioacetate (1235 mg, 10.81 mmol). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. The mixture was diluted with ethyl acetate, washed with water (3 times), brine, and dried (MgSO4), filtered and concentrated. The crude product was purified on Biotage SP1 (40+M equilibrated), eluting with 20-80% ethyl acetate/hexanes, 20 CV (CV stands for column volume). LC/MS: [(M+1)]+=465.2;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CO)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
To a solution of 3-fluoro-4-nitrobenzoic acid (2.0 g, 10.8 mmol) in THF (50 ml) at 0° C. was added BH3.Me2S complex (2.215 ml, 22.15 mmol) drop-wise. The mixture was stirred at 0° C. for 3 h, and was then stirred at 65° C. for 18 h. To the cooled mixture was added ice (50 g), followed by 1 N aq. HCl (100 ml), and the resulting mixture was extracted with EtOAc (200 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound as a white solid (1.79 g, 97%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=C(C=CC=3)C(O)=O)[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.FC1C=C(N)C(N)=CC=1F.[Br:46]C1C=CC=CC=1C(O)=O>>[Br:46][C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[C:8]1[NH:12][C:11]2[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=2[N:9]=1
Reactant: O=C(O)c1ccccc1Br
Reactant: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Agent: Nc1cc(F)c(F)cc1N
Product: Fc1cc2nc(-c3ccccc3Br)[nH]c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, intermediate c, from 4,5-difluoro-benzene-1,2-diamine (CAS Reg. No. 76179-40-3) and 2-bromo-benzoic acid (CAS Reg. No. 88-65-3). Yellow solid (85%). MS (Turbo Spray): m/z=273.0 (M+H).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH:9]=[CH:8][N:7]=2)=[N:4][N:3]=[N:2]1.[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([O:12][C:10]3[CH:9]=[CH:8][N:7]=[C:6]([C:5]4[NH:1][N:2]=[N:3][N:4]=4)[CH:11]=3)=[CH:18][CH:17]=2)=[O:30])=[CH:24][CH:23]=1)[CH3:21]
Reactant: Nc1ccc(Oc2ccnc(-c3nnn[nH]3)c2)cc1
Reactant: CCc1ccc(N=C=O)cc1
Product: CCc1ccc(NC(=O)Nc2ccc(Oc3ccnc(-c4nnn[nH]4)c3)cc2)cc1
Reaction time: 4 h

Procedure:
The title compound is prepared as described In Example 102 but using 4-[2-(1H-tetrazol-5-yl)-pyridin-4-yloxy]-phenylamine (Example 122) and 4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 4 h. The crude product is washed with a solution of CH2Cl2/MeOH (95/5) and dried in vacuo to afford the title compound as a beige solid: ES-MS: 402.0 [M+H]+; single peak at tR=7.73 min (System 2); Rf=0.20 (CH2Cl2/MeOH, 80/20).