Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]([C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])[C:4]2[C:13]3[CH:12]=[C:11]([O:14][CH3:15])[C:10]([C:16]4[C:17]([CH3:22])=[N:18][O:19][C:20]=4[CH3:21])=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:23]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.O>CN1C(=O)CCC1>[CH3:22][C:17]1[C:16]([C:10]2[C:11]([O:14][CH3:15])=[CH:12][C:13]3[C:4]4[N:3]([C@@H:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH3:25])[C:2]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[N:23][C:5]=4[CH:6]=[N:7][C:8]=3[CH:9]=2)=[C:20]([CH3:21])[O:19][N:18]=1
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(Cl)n([C@H](C)c3ccccc3)c12
Reactant: C1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(N3CCCCC3)n([C@H](C)c3ccccc3)c12
Temperature: 150 °C
Yield: 53.6 %

Procedure:
2-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinoline (30 mg, 0.069 mmol) (for a preparation see Intermediate 12) was dissolved in NMP (0.5 ml), piperidine (0.2 ml, 2.020 mmol) was added and the mixture was heated at 150° C. for 30 min, then cooled, added to water (10 ml) and extracted with EtOAc (10 ml). The solvent was washed with water (2×10 ml), dried and evaporated. The residue was dissolved in DCM (2 ml), loaded onto a 10 g silica column, eluted with 2M methanolic ammonia/DCM (0-10%) and product-containing fractions evaporated in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-2-(1-piperidinyl)-1H-imidazo[4,5-c]quinoline (18 mg, 0.037 mmol, 53.9% yield) as a amber solid. LCMS (formate) Rt 1.05 min, MH+ 482
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:16](=[O:18])(=[O:17])[NH:15][C:14](=[O:19])[CH2:13]1)[C:5](OC)=[O:6].[BH4-].[Li+]>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:9]=[CH:10][C:11]=1[CH:12]1[S:16](=[O:17])(=[O:18])[NH:15][C:14](=[O:19])[CH2:13]1
Reactant: COC(=O)c1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CC(c2ccc(CO)cc2Br)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a solution of methyl 3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)benzoate (77.0 mg, 0.221 mmol) in tetrahydrofuran (6 mL) was added 2 M lithium tetrahydroborate in tetrahydrofuran (332 μL) at room temperature. The resulting solution was stirred at room temperature overnight. The reaction solution was diluted with methanol, and stirred for 0.5 h. The crude material was purified by preparative LCMS to give a white solid (65 mg, 92%). 1H NMR (400 MHz, CD3OD): δ 7.57 (s, 1H), 7.46 (m, 2H), 5.30 (dd, J=9.0, 5.9 Hz, 1H), 4.49 (s, 2H), 3.26 (m, 1H), 2.97 (dd, J=17.2, 5.7 Hz, 1H). LCMS found for C10H10BrNO4SNa (M+Na)+: m/z=342, 344.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:32])[F:31])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1.C(N(CC)CC)C.[CH3:49][N:50]([CH3:55])[S:51](Cl)(=[O:53])=[O:52].O.NN>CN(C=O)C>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:37][CH2:38][N:39]([S:51](=[O:53])(=[O:52])[N:50]([CH3:55])[CH3:49])[CH2:40][CH2:41]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:31])([F:32])[F:33])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1
Reactant: O=C(Nc1ccc2cn[nH]c2c1)c1cc2nc(Nc3ccccc3C(F)(F)F)[nH]c2cc1N1CCNCC1
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Agent: NN
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)N1CCN(c2cc3[nH]c(Nc4ccccc4C(F)(F)F)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide trihydrochloride (0.3 mmol; see Example 88) in DMF (1 mL) was added with triethylamine (1.5 mmol) and N,N-dimethylsulfamoyl chloride (0.4 mmol). The resulting mixture was stirred at RT for 4 h and added with hydrazine hydrate (2 mmol). The contents were warmed to 50° C. and stirred vigorously for 60 min. The reaction mixture was then poured into ice cold water, and the solid was filtered, washed with water, and dried under vacuum. The crude product was then purified on a silica gel column chromatography using MeOH/DCM as eluent to afford 6-(4-dimethylsulfamoyl-piperazin-1-yl)-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide as a white solid. MS: m/z 628 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[C:5](Br)=[C:4]([CH3:14])[CH:3]=1.[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[C:24]([O-])([O-])=O.[Cs+].[Cs+].O>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>[NH2:1][C:2]1[C:10]2[O:9][CH:8]([CH:11]([OH:12])[CH3:24])[CH2:7][C:6]=2[C:5]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)=[C:4]([CH3:14])[CH:3]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1cc(N)c2c(c1Br)CC(CO)O2
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N)c2c(c1-c1ccncc1)CC(C(C)O)O2
Temperature: 135 °C
Reaction time: 1 h

Procedure:
A mixture of (7-amino-4-bromo-5-methyl-2,3-dihydrobenzofuran-2-yl)methanol (7e) (1.7 g, 6.6 mmol), pyridin-4-ylboronic acid (1.6 g, 1.3 mmol), Cs2CO3 (5.3 g, 16 mmol), Pd(PPh3)4 (0.76 g, 0.66 mmol) and water (13 mL) in DMF (60 mL) was stirred at 135° C. under N2 for 1 h. It was cooled to ambient temperature, poured into water (100 mL), extracted with EtOAc (150 mL), washed with water, brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (20:1 to 5:1 to 1:1) to give the title compound (7f) as a yellow solid. MS-ESI (m/z): 257 (M+1)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]([C:15]2([C:18]3[CH:28]=[CH:27][C:21]4[O:22][C:23]([F:26])([F:25])[O:24][C:20]=4[CH:19]=3)[CH2:17][CH2:16]2)=[O:14])[N:3]=1.[C:29]([O:33][C:34]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=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>[F:25][C:23]1([F:26])[O:22][C:21]2[CH:27]=[CH:28][C:18]([C:15]3([C:13]([NH:12][C:4]4[N:3]=[C:2]([C:40]5[CH:41]=[C:36]([CH:37]=[CH:38][CH:39]=5)[C:34]([O:33][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:35])[C:11]5[C:6]([CH:5]=4)=[CH:7][CH:8]=[CH:9][CH:10]=5)=[O:14])[CH2:17][CH2:16]3)=[CH:19][C:20]=2[O:24]1
Reactant: O=C(Nc1cc2ccccc2c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Temperature: 80 °C
Yield: 97.1 %

Procedure:
To N-(1-bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (508 mg, 1.14 mmol) in 1,2-dimethoxyethane (11 mL) was added 3-(tert-butoxycarbonyl)phenylboronic acid (328 mg, 1.48 mmol), tetrakis(triphenylphosphine)palladium (0) (131 mg, 0.114 mmol), and 2 M Na2CO3 (1.71 mL, 3.41 mmol). The mixture was heated at 80° C. overnight before it was diluted with ethyl acetate (10 mL) and washed with water (20 mL). The organics were dried over Na2SO4 and evaporated. The resulting crude material was purified by silica gel chromatography eluting with 0-10% ethyl acetate in hexanes to yield tert-butyl 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoate (603 mg, 97%). ESI-MS m/z calc. 544.6. found 545.3 (M+1)+. Retention time 2.76 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:4].CCN(C(C)C)C(C)C.[Si:30](Cl)([CH3:33])([CH3:32])[CH3:31].CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C)CN1C(=O)OCc1ccccc1
Yield: 97.5 %

Procedure:
Dissolved (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester 1.5 g (5.37 mmol) in 10 mL of THF was treated with DIEA 1.31 mL (7.51 mmol) and 0.89 mL of TMS-Cl (6.98 mmol) added drop-wise while stirring. After 2 h of stirring, 50 mL of EtOAc was added and the mix was washed with Sat. NaHCO3 (3×50 mL). The organic layer was then dried over Na2SO4, filter through silica and concentrated to afford 1.84 g (97%) of (2S,4R)-4-Trimethylsilanyloxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester as a clear oil. HPLC: Rt 4.12 min. (100% area). 1H NMR (CDCl3, 400 MHz) δ: 7.37-7.28 (5H, m), 5.22-5.01 (2H, m), 4.51-4.41 (2H, m), 3.76 (2H, s), 3.70-3.66 (1H, m), 3.51-3.39.(1H, m), 2.22-2.16 (1H, m), 2.04 (3H, s), 0.11 (9H, s).
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.Cl.N1CCOCC1.O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]=[O:25])=[CH:19][CH:18]=1>O1CCOCC1>[OH:25][CH:24]1[O:6][C:2](=[O:5])[CH:3]=[C:23]1[C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1
Reactant: O=CC(=O)O
Reactant: COc1ccc(CC=O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1COCCN1
Solvent: O
Product: COc1ccc(C2=CC(=O)OC2O)cc1
Yield: 97.8 %

Procedure:
A suspension of glyoxalic acid hydrate (2.45 g, 26.6 mmol) and morpholine hydrochloride (3.28 g, 26.35 mmol) in dioxane (25 mL) was stirred as water (2 mL) was added. The homogeneous solution and 4-methoxyphenyl acetaldehyde (3.8 g, 25.3 mmol) was then added and the solution was stirred at reflux for 24 h. The solvent was evaporated and a solid was formed after addition of 20 mL of water. The solid was collected and washed with water to give 5.1 g (98%) of the product: MS m/z 189 (M−17+H).
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]2[C@@H:8]3[O:10][C@@H:9]3[C@H:3]1[CH2:4][CH:5]([O:11][C:12]([C:14]([OH:25])([C:20]1[S:24][CH:23]=[CH:22][CH:21]=1)[C:15]1[S:19][CH:18]=[CH:17][CH:16]=1)=[O:13])[CH2:6]2.[CH3:26][O:27][S:28]([O:31]C)(=[O:30])=[O:29]>C(#N)C>[CH3:1][N+:2]1([CH3:26])[C@@H:3]2[C@@H:9]3[O:10][C@@H:8]3[C@H:7]1[CH2:6][C@@H:5]([O:11][C:12]([C:14]([OH:25])([C:15]1[S:19][CH:18]=[CH:17][CH:16]=1)[C:20]1[S:24][CH:23]=[CH:22][CH:21]=1)=[O:13])[CH2:4]2.[CH3:26][O:27][S:28]([O-:31])(=[O:30])=[O:29]
Reactant: COS(=O)(=O)OC
Reactant: CN1[C@@H]2CC(OC(=O)C(O)(c3cccs3)c3cccs3)C[C@H]1[C@@H]1O[C@@H]12
Solvent: CC#N
Product: COS(=O)(=O)[O-]
Product: C[N+]1(C)[C@@H]2C[C@@H](OC(=O)C(O)(c3cccs3)c3cccs3)C[C@H]1[C@@H]1O[C@@H]12

Procedure:
Analogously to the method described in para. 1.2, 75.5 g scopine di-(2-thienyl)glycolate are reacted with 20.9 ml dimethylsulphate in 750 ml acetonitrile.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[NH3:16]>C1C=CC=CC=1.O1CCCC1>[C:1]([C:4]1[S:8][C:7]([C:9]([NH2:16])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)s1
Reactant: N
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(=O)c1ccc(C(N)=O)s1
Reaction time: 1.5 h

Procedure:
A mixture of 5-acetylthiophene-2-carboxylic acid (5.6 g) and thionyl chloride (5.25 ml) in benzene (70 ml) was refluxed for 3 h; a further portion of thionyl chloride (5.3 ml) was added and reflux continued for 1.5 h. The resulting solution was evaporated to leave a white solid which was dissolved in tetrahydrofuran (70 ml). Aqueous ammonia (s.g. 0.88; 6 ml) was added and the reaction mixture was stirred for 1 h. The white precipitate was washed with water, leaving the title amide (3.43 g) mp 231°-233°. TLC SiO2 (EtOAc) Rf 0.28.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH2:19])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[CH2:30][NH2:31]>>[NH2:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([S:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:31][CH2:30][C:23]3[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=3[O:21][CH3:20])[CH:7]=2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(Sc2ccnc(Cl)c2)c2ccccc12
Reactant: COc1ccc(CN)c(OC)c1
Product: COc1ccc(CNc2cc(Sc3ccc(N)c4ccccc34)ccn2)c(OC)c1
Temperature: 120 °C
Yield: 38.6 %

Procedure:
A mixture of 4-(2-chloropyridin-4-ylthio)naphthalen-1-amine (1.40 g, 90% purity, 4.40 mmol) and (2,4-dimethoxyphenyl)methanamine (3.7 mL, 24 mmol) was heated together at 120° C. for 24 hr. The reaction mixture was loaded directly onto silica and purified by flash column chromatography (SiO2, 80 g, EtOAc in isohexane, 30-70%, gradient elution) to afford 4-(4-aminonaphthalen-1-ylthio)-N-(2,4-dimethoxybenzyl)pyridin-2-amine as a dark red oil (710 mg, 37%); Rt 1.74 min (Method 2); m/z 418 (M+H)+ (ES+).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:7][C:8](O)=[O:9])[CH2:3][C:4](O)=[O:5].B.C1COCC1.Cl>O1CCCC1>[CH3:1][C:2]([CH3:11])([CH2:7][CH2:8][OH:9])[CH2:3][CH2:4][OH:5]
Reactant: CC(C)(CC(=O)O)CC(=O)O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(CCO)CCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.5 %

Procedure:
Step A To the solution of 3,3-dimethylglutaric acid (Aldrich) (5.1 g, 32 mmol) in anhydrous tetrahydrofuran (100 mL) at 0° C. was added a solution of BH3.THF (1 M, 100 mL, 100 mmol). The reaction mixture was stirred at room temperature for 18 h. Aqueous HCl solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc) to give 3,3-dimethyl-pentane-1,5-diol as a colorless oil (1.5 g, 34%).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[NH2:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[F:8][C:7]1[C:2]([O:30][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][N:21]=[C:20]3[NH:12][C:13]2[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=2)=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1cccc(F)c1F
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Cn1ccc(N)n1
Product: CC(=O)c1cccc(F)c1Oc1ccc2ncnc(Nc3ccn(C)n3)c2c1

Procedure:
The compound of Example 134 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 1-(2,3-difluoro phenyl)ethanone, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([CH3:12])[C:7](=[O:13])[C:6]=2[CH:14]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:31]=1)[C:20]([NH:22][C:23]1[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[F:1][C:2]1[C:3]([O:16][C:17]2[CH:18]=[C:19]([CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:31]=2)[C:20]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=2)=[O:21])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([CH3:12])[C:7](=[O:13])[C:6]=2[CH:14]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CN1CCOc2cc(F)c(F)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC[C@H](C)Oc1cc(Oc2cc3c(cc2F)C(=O)N(C)CCO3)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Yield: 6.6 %

Procedure:
A mixture of 7,8-difluoro-4-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (725 mg, 2.0 mmol), 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (600 mg, 1.97 mmol) and potassium carbonate (550 mg, 3.88 mmol) in DMA (10 mL) was heated to 160° C. for 5 hours. Water (20 mL) was added to the reaction and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with water (2×30 mL) and brine (2×30 mL), dried (MgSO4), filtered and evaporated to give a yellow oil. This was purified by column chromatography on silica, eluting with 20-100% ethyl acetate in isohexane, to give the desired compound as a foam (65 mg).
Reaction SMILES: Br[CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([OH:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([OH:5])=[O:4].[OH-].[NH4+:18]>>[NH2:18][CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([OH:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([OH:5])=[O:4]
Reactant: [NH4+]
Reactant: O=C(O)C(Br)C12CC3CC(CC(O)(C3)C1)C2
Agent: [OH-]
Product: NC(C(=O)O)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
α-Bromo-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula Q) is then dissolved in ammonium hydroxide, preferably 30% ammonium hydroxide and the reaction mixture is heated preferably to 65° C. The reaction mixture is then concentrated to a solid. EtOH is then added and the reaction is again concentrated to yield a racemic mixture comprising (<aS)-<a-amino-3-hydroxytricyclo[3.3.1.1 3,7]decane-1-acetic acid (Formula V). See also Example 19 herein.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([C:22]2[CH:27]=[C:26]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:25]=[C:24]([F:35])[CH:23]=2)([N+:20]#[C-])[CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:36][CH:37]([CH3:39])[CH3:38].Cl>CO.O1CCOCC1>[NH2:20][C@:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:36][CH:37]([CH3:39])[CH3:38])[CH:4]=1)([C:22]1[CH:27]=[C:26]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:25]=[C:24]([F:35])[CH:23]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1
Reactant: [C-]#[N+][C@@](Cc1ccc(C(=O)OC)cc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(OC(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccc(C[C@](N)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(F)c(OC(C)C)c2)cc1
Reaction time: 0.05 h
Yield: 86.5 %

Procedure:
To a solution of (R)-methyl 4-(2-(4-fluoro-3-isopropoxyphenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-isocyanoethyl)benzoate (120 mg, 0.22 mmol) in MeOH (2 mL) was added 4 N HCl in dioxane (0.5 mL) and the reaction mixture was stirred for 3 minutes. The reaction solvent was evaporated under a stream of nitrogen. The residue was diluted with EtOAc (15 mL), washed with saturated sodium bicarbonate solution (10 mL) and sat. NaCl, dried over MgSO4, filtered and evaporated to yield (R)-methyl 4-(2-amino-2-(4-fluoro-3-isopropoxyphenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)benzoate (103 mg, 86% yield) as a clear glass. LCMS: RT=1.87 min [M−NH2] 525.1 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[N:4][CH:3]=1.[CH2:9]1COCC1.C[Mg+].[Br-]>C(OCC)C>[Br:1][C:2]1[S:6][C:5]([CH:7]([OH:8])[CH3:9])=[N:4][CH:3]=1
Reactant: O=Cc1ncc(Br)s1
Reactant: C1CCOC1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(O)c1ncc(Br)s1
Temperature: 0 °C

Procedure:
To an ice cold solution of 5-bromothiazole-2-carbaldehyde (3 g, 15.6 mmol) in diethyl ether (20 mL) was added a THF solution of MeMgBr (3M, 50 ml, 150 mmol). Solid was produced rapidly. LCMS showed a new product with desired mass. The reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ISCO CombiFlash® chromatography eluting 10-40% ethyl acetate in heptanes. The title compound was obtained as a viscous yellow oil (3.25 g, 62% yield).
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][CH:7]=1)[CH3:2].Br[C:19]1[CH:20]=[C:21]([CH:24]=[C:25](Br)[CH:26]=1)[CH:22]=[O:23]>O1CCCC1.C(N(CC)CC)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.[Cu]I>[CH2:1]([CH:3]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([C:13]#[C:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][CH:8]=3)[CH:26]=2)[CH:22]=[O:23])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=Cc1cc(Br)cc(Br)c1
Reactant: C#Cc1ccc(OCC(CC)CCCC)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC(CC)COc1ccc(C#Cc2cc(C#Cc3ccc(OCC(CC)CCCC)cc3)cc(C=O)c2)cc1
Temperature: 70 °C
Reaction time: 23 h
Yield: 79.3 %

Procedure:
Nitrogen was bubbled through a solution of 1-(2-Ethylhexyloxy)-4-ethynylbenzene (4) (1.69 g, 7.34 mmol) and 3,5-dibromobenzaldehyde (5) (692 mg, 2.62 mmol) in tetrahydrofuran (33 mL) and triethylamine (50 mL) for 5 min. Tetrakis(triphenylphosphine)palladium(0) (218 mg, 0.189 mmol) and copper(I) iodide (65 mg, 0.34 mmol) were added and nitrogen bubbled through the solution for a further 5 min, before stirring at 70° C. for 23 h. Once cool, the solvent was removed and the residue purified by column chromatography over silica with dichloromethane-light petroleum (1:2 to 1:1) as eluent to leave 3,5-bis[4-(2-ethylhexyloxy)phenylethynyl]benzaldehyde (6) (1.17 g, 79%) as a pale brown oil. (Found: C, 83.3; H, 8.2; C39H46O3 requires C, 83.2; H, 8.2%); νmax(film)/cm−1 2211 (C≡C) and 1704 (C═O); δH(400 MHz, CDCl3) 0.93-0.99 (12 H, m, CH3), 1.28-1.56 (16 H, m, CHCH2CH2CH2CH3 and CHCH2CH3), 1.75 (2 H, m, OCH2CH), 3.87 (4 H, d, J 6, OCH2CH), 6.90 (4 H, AA′BB′), 7.48 (4 H, AA′BB′), 7.87 (1 H, dd, J 1.5, 4-H), 7.92 (2 H, d, J 1.5, 2, 6-H) and 10.00 (1 H, s, CHO); δc(100.6 MHz, CDCl3) 11.1, 14.1, 23.1, 23.8, 29.0, 30.4, 39.3, 70.6, 86.0, 91.7, 114.1, 114.6, 125.2, 131.3, 133.5, 136.6, 139.1, 159.9 and 191.0.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]([O:10][C:11](=[O:13])[CH3:12])(=O)[CH3:8].O[C@@H]([C-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1)C.[CH-]1C=CC=C1.[Fe+2:27]>>[C:11]([O:10][C@@H:7]([C-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1)[CH3:8])(=[O:13])[CH3:12].[CH-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.[Fe+2:27]
Reactant: c1ccncc1
Reactant: C[C@@H](O)[c-]1cccc1
Reactant: CC(=O)OC(C)=O
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Product: CC(=O)O[C@H](C)[c-]1cccc1
Reaction time: 20 h

Procedure:
500 g (6.32 mol) of pyridine and subsequently 600 g (5.88 mol) of acetic anhydride were added dropwise while stirring to the crude (R)-(1-hydroxyethyl) ferrocene from Example 1 at 25° C. under argon. The reaction mixture was allowed to stand for a further 20 hours at 25° C., then hydrolysed with 1.5 l of ammonium chloride solution (20%) and extracted three times with 1.5 l each time of ethyl acetate. The solvent was distilled off from the combined organic phases.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([CH3:8])[O:4][N:3]=1.[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>>[Br:7][C:6]1[C:2]([NH:1][S:15]([C:12]2[CH:11]=[CH:10][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)(=[O:17])=[O:16])=[N:3][O:4][C:5]=1[CH3:8]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Cc1onc(N)c1Br
Product: Cc1onc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)c1Br

Procedure:
N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylsulfonamide was prepared, using the method in Example 193b, from 3-amino-4-bromo-5-methylisoxazole and 4-biphenylsulfonyl chloride in 5% yield. The crude product was purified by column chromatography. After recrystallization from ethyl acetate/hexanes, N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylsulfonamide (m.p. 154-156° C.) was obtained in 51% yield.