Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][C:41]([NH2:43])=[S:42])[CH2:4][CH2:3]2.C(N(CC)C(C)C)(C)C.Br[CH:54]([CH3:58])[C:55](=O)[CH3:56].O>CN(C=O)C>[CH3:58][C:54]1[N:43]=[C:41]([NH:40][C@:5]23[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]2[C@@H:7]2[C@@:2]([CH3:1])([CH2:3][CH2:4]3)[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)[S:42][C:55]=1[CH3:56]
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(N)=S)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(=O)C(C)Br
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=C(C)[C@@H]1CC[C@]2(Nc3nc(C)c(C)s3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-thioureido-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (150 mg, 0.249 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine (0.173 mL, 0.995 mmol) and 3-bromobutan-2-one (56.4 mg, 0.373 mmol). The reaction mixture was stirred at rt. After 18 h, the reaction mixture was poured into a separatory funnel containing H2O (10 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to white solid. The material was redissolved in DCM (5 mL) and MeOH was added to effect precipitation. The mixture was concentrated to remove most of DCM and the resulting white precipitate was filtered, washed with cold MeOH, and dried in a vacuum oven to give methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4,5-dimethylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (121 mg, 0.175 mmol, 70.5% yield) as a white solid. LCMS: m/e 655.3 (M+H)+, 2.72 min (method 2). 1H NMR (500 MHz, CHLOROFORM-d) δ 7.95 (d, J=8.2 Hz, 2H), 7.21 (d, J=8.2 Hz, 2H), 5.31 (d, J=4.6 Hz, 1H), 4.76 (br. s., 1H), 4.65 (s, 1H), 3.93 (s, 3H), 2.43 (d, J=10.4 Hz, 1H), 2.21 (s, 3H), 2.15 (s, 3H), 2.11 (d, J=6.7 Hz, 1H), 2.07-1.96 (m, 1H), 1.80-1.65 (m, 6H), 1.57-1.36 (m, 8H), 1.35-1.27 (m, 2H), 1.23 (d, J=10.1 Hz, 1H), 1.17-1.11 (m, 1H), 1.09 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H), 0.94 (s, 6H).
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=2)(=[O:29])=[O:28])=[CH:13][CH:12]=1)=[O:10])(C)(C)C>C(O)=O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C:9]([NH:8][CH2:7][C:6]([OH:41])=[O:5])=[O:10])=[CH:16][CH:15]=2)=[C:20]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:38])([F:39])[F:40])[CH:31]=2)(=[O:29])=[O:28])[CH:21]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: O=CO
Product: O=C(O)CNC(=O)c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl({[4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino) phenyl]sulfanyl}methyl)phenyl]carbonyl}amino)acetate (90 mg, 0.14 mmol) in formic acid (2 ml) was stirred at room temperature overnight. Formic acid was removed under vacuum and the desired product (72 mg, 88%) was re-crystallized from 10% MeOH in CH2Cl2.
Reaction SMILES: [CH:1]([N:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]2[N:19]([C:27]3[C:28]4[C@H:35]([CH:36]([CH3:38])[CH3:37])[CH2:34][CH2:33][C:29]=4[N:30]=[CH:31][N:32]=3)[CH2:20][C:21]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:14]=12)C(=O)OC(C)(C)C)([CH3:3])[CH3:2].[ClH:39]>C(Cl)Cl.O1CCOCC1>[ClH:39].[ClH:39].[ClH:39].[CH:36]([C@H:35]1[C:28]2[C:27]([N:19]3[C:15]4[C:14](=[C:13]([CH2:12][NH:4][CH:1]([CH3:3])[CH3:2])[CH:18]=[CH:17][CH:16]=4)[C:21]4([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH2:20]3)=[N:32][CH:31]=[N:30][C:29]=2[CH2:33][CH2:34]1)([CH3:38])[CH3:37]
Reactant: CC(C)[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c(CN(C(=O)OC(C)(C)C)C(C)C)cccc43)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)NCc1cccc2c1C1(CCNCC1)CN2c1ncnc2c1[C@H](C(C)C)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of (S)-tert-butyl isopropyl((1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)carbamate (0.0189 g, 0.0364 mmol) in DCM (2 mL) was treated with 4N HCl in dioxane (0.5 mL). The reaction was stirred at room temperature for 1 hour and concentrated under reduced pressure to give (S)—N-((1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine trihydrochloride (0.020 g, 100%). LCMS (APCI+) m/z 420.3 [M+H]+; Rt=3.14 min.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:23])[CH:15]=[C:16]([CH2:21]O)[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS([Cl:40])(=O)=O.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:23])[CH:15]=[C:16]([CH2:21][Cl:40])[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)cc(I)c21
Agent: CN(C)c1ccncc1
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)cc(I)c21
Temperature: 65 °C
Yield: 93 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(hydroxymethyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (4.89 g), DMAP (209 mg) and collidine (1.59 mL) in 173 mL anhydrous DMF is heated to 65° C. to solubilize the starting material. To this solution is added methanesulfonyl chloride (2.77 mL) at room temperature. The reaction is heated at 65° C. for 2 h, then allowed to cool to room temperature. The reaction is poured into H2O (300 mL) to precipitate the product. The solid is filtered and recrystallized from CH2Cl2/hexanes to afford 4.74 g (93%) of the desired product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.[BH4-].[Na+]>CCO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([O:10][C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(Br)cc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-bromo-2-(trifluoromethoxy)benzaldehyde (5.0 g, 19 mmol) from Step 1 above in EtOH (100 mL) at 0° C. was added NaBH4 (0.88 g, 23 mmol). The mixture was stirred for 1 h at 0° C., the cooling bath was removed, and the solution was stirred at ambient temperature for 14 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 (75 mL). The organic phase was separated, dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 5-10% EtOAc:hexanes. 4-Bromo-2-(trifluoromethoxy)benzyl alcohol was obtained as an amorphous solid by evaporation from CH2Cl2 (TLC Rf =0.25 (10% EtOAc:hexanes); HPLC retention time=8.8 min (method A)).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]=[O:15]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C(C(C)=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][C:14]([NH:13][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOC(=O)CN=C=O
Reactant: Cc1ccc2cccc(O)c2n1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCC(C)=O
Product: CCOC(=O)CNC(=O)Oc1cccc2ccc(C)nc12

Procedure:
A mixture of 15.9 g of 2-methyl-8-hydroxyquinoline, 13.6 g of ethyl isocyanatoacetate and 10 drops of dibutyltin dilaurate in 200 ml of methyl ethyl ketone was heated at reflux temperature for seven hours, after which the solvent was removed by evaporation in vacuo leaving a solid residue. The residue was recrystallized from toluene to give the desired ethyl N-(((2-methyl-8-quinolinyl)oxy)carbonyl)glycinate as light tan crystals, m.p. 118°-120° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([C:22](=[O:24])[NH2:23])=[CH:16]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].N1C2C(=CC=CC=2C(C2C=CC=CC=2)CC(NC)=O)C=C1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([C:22](=[O:24])[NH2:23])=[CH:16]2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]c(C(N)=O)cc2c1
Agent: CNC(=O)CC(c1ccccc1)c1cccc2cc[nH]c12
Product: CCOC(=O)CC(c1ccccc1)c1ccc2[nH]c(C(N)=O)cc2c1

Procedure:
3-(2-Carbamoyl-1H-indol-5-yl)-3-phenyl-propionic acid ethyl ester CII (628 mg) was prepared from 3-(2-carbamoyl-1H-indol-5-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described above for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-propionamide XIX (Example 4).
Reaction SMILES: C1(N(C2C=CC=CC=2)C([O:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[C:16]3[CH2:22][CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=O)=O)C=CC=CC=1.[F:41][C:42]([F:46])([F:45])[CH2:43][NH2:44]>>[F:41][C:42]([F:46])([F:45])[CH2:43][NH:44][C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH2:22][CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:10]
Reactant: O=C(NCCc1c[nH]c2ccc(C(=O)OC(=O)N(c3ccccc3)c3ccccc3)cc12)OCc1ccccc1
Reactant: NCC(F)(F)F
Product: O=C(NCCc1c[nH]c2ccc(C(=O)NCC(F)(F)F)cc12)OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of [2-[5-[[[(diphenylamino)carbonyl]oxy]carbonyl]-1H-indol-3-yl]ethyl]carbamic acid, phenylmethyl ester (0.5 g) and 2,2,2-trifluoroethylamine (0.4 ml) was heated at 100° C. for 10 mins. in an autoclave. The mixture was cooled in an ice bath and triturated with cyclohexane (70 ml) to give a cream solid (0.3 g) which was crystallised from ethyl acetate and cyclohexane to give the title compound as an off-white crystalline solid (0.2 g) m.p. 138°-140° C.
Reaction SMILES: B.CSC.[C:5]([C-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(=[O:7])[CH3:6].[C-:13]1([C:18](=[O:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14]1.[Fe+2:21]>O1CCCC1>[OH:7][C@@H:5]([C-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)[CH3:6].[C-:13]1([C@H:18]([OH:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14]1.[Fe+2:21]
Reactant: CC(=O)[c-]1cccc1
Agent: [Fe+2]
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@@H](O)[c-]1cccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
11.5 ml (115 mmol) of borane-dimethyl sulphide adduct were added dropwise at 20° C. to a solution of 30.0 g (111 mmol) of 1,1'-diacetylferrocene and 13.5 ml (13.5 mmol, 0.12 eq) of catalyst (S)-III (R6 =CH3) in 200 ml of tetrahydrofuran over a period of 45 minutes. After 1 hour at 20°-25° C., the reaction mixture was poured while stirring vigorously onto about 600 ml of ice/water and stirred for 0.5 hour. The aqueous phase was subsequently extracted three times with 200 ml each time of tert-butyl methyl ether, the combined organic phases were dried over magnesium sulphate and evaporated in a high vacuum. This gave 32.7 g (107%) of the crude title compound. This crude product can be used without further purification for the further reactions. Recrystallization from hexane gave (R,R)-1,1'-bis(1-hydroxyethyl)ferrocene as a yellow crystalline solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1>>[C:37]([O:36][C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:9]2[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:6]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:23][CH:24]=1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(C(=O)OCC)c(C(=O)OCC)[nH]1
Product: CCCCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 96.6 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 8.0 g of diethyl 2-butylimidazole-4,5-dicarboxylate (prepared as described in Preparation 3) and 10.41 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate, 15.4 g of the title compound were obtained as a gum.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=O)=[C:4](F)[CH:3]=1.[NH:19](C(OC(C)(C)C)=O)[NH2:20].C(O)(=O)C>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:9]([C:11]3[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=3)=[N:19][NH:20]2)=[CH:6][C:7]=1[F:8]
Reactant: O=C(c1ccc(Cl)nc1)c1cc(F)c(Br)cc1F
Reactant: CC(C)(C)OC(=O)NN
Solvent: CC(=O)O
Solvent: CO
Product: Fc1cc2c(-c3ccc(Cl)nc3)n[nH]c2cc1Br
Temperature: 150 °C
Yield: 23.2 %

Procedure:
Impure (4-bromo-2,5-difluorophenyl)(6-chloro-3-pyridinyl)methanone (0.548 g) in methanol (2 ml) was stirred with 1,1-dimethylethyl hydrazinecarboxylate (0.152 g) and acetic acid (100 μl) for 20 h. The crude mixture was partitioned between sodium bicarbonate and chloroform. The organic layer was separated using a hydrophobic filter tube and the solvent was removed under vacuum. The crude material in THF (1 ml) was treated with DBU (0.358 ml) and heated in a sealed tube in a microwave oven at 150° C. for 30 min. The reaction mixture was cooled and partitioned between ethyl acetate and 0.5M aqueous hydrochloric acid. The organic layer was washed with water then brine then separated using a hydrophobic filter tube. The organic phase was concentrated under vacuum and the residue was purifiedon a silica SPE cartridge (50 g) eluting with cyclohexane/ethyl acetate (100:0 to 0:100) to give the title compound (87 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:17]3[CH:18]=[C:19]([C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=4)=[O:23])[CH:20]=[CH:21][C:16]=3[O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:34][C:35]1C=C(S(Cl)(=O)=O)C=C(C)C=1>>[CH2:34]([O:30][C:29](=[O:31])[C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]([S:9]([C:4]4[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=4)(=[O:11])=[O:10])[C:17]=3[CH:18]=2)=[O:23])=[CH:33][CH:32]=1)[CH3:35]
Reactant: Cc1cc(C)cc(S(=O)(=O)N2CCOc3ccc(C(=O)Nc4ccc(C(=O)O)cc4)cc32)c1
Reactant: Cc1cc(C)cc(S(=O)(=O)Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)cc(C)c2)CCO3)cc1

Procedure:
4-{[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=466.5 (M−H), was prepared as described for example 14, steps 1 to 8. Step 7 was performed using 3,5-dimethyl-benzenesulfonyl chloride and yielded 4-{[4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.F[C:11]1[CH:19]=[N:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:16]2[CH:17]=[N:18][CH:19]=[CH:11][C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccncc1F
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(CNc2cnccc2C(=O)O)cc1
Yield: 51 %

Procedure:
The title compound was prepared in 51% yield from 4-methylbenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.41 (br s, 1H), 8.13 (s, 1H), 7.81 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.25 (d, 2H, J=7.9 Hz), 7.15 (d, 2H, J=7.8 Hz), 4.50 (s, 2H), 2.28 (s, 3H). [M+H] calc'd for C14H14N2O2, 243; found 243.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1>CN(C)C=O>[Si:16]([O:14][CH2:13][C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:15])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](CO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Yield: 97.2 %

Procedure:
A procedure similar to that described in Preparation 8 was repeated, except that 7.00 g of (S)-2-benzyloxycarbonylaminopropanol (prepared as described in Preparation 31), 6.03 g of t-butyldimethylsilyl chloride, 5.45 g of imidazole and 100 ml of anhydrous dimethylformamide were used, to give 10.52 g of the title compound having an Rf value of 0.48 (on silica gel thin layer chromatography, using a 1:7 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.Cl[C:9]1[C:28]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)=[CH:27][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([Cl:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[O:14])=[CH:11][N:10]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:26][C:23]([F:24])([F:25])[O:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:27]=[C:28]([C:29]3[CH:34]=[N:33][CH:32]=[N:31][CH:30]=3)[C:9]([O:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[N:10][CH:11]=2)=[CH:21][CH:20]=1
Reactant: OC1CCOCC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2cncnc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(OC2CCOCC2)c(-c2cncnc2)c1
Temperature: 120 °C
Reaction time: 26 h

Procedure:
Tetrahydro-2H-pyran-4-ol (0.105 mL, 1.095 mmol) was added to a stirred mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide (Example 76, 100 mg, 0.243 mmol) and K2CO3 (201.6 mg, 1.458 mmol) in MeCN (1 mL) and the RM was stirred at 110-130° C. for 26 h. The solvent was evaporated off under reduced pressure and the crude product was purified by SFC (Column 2-EP; gradient 9% to 19% in 6 min.) and lyophilized in water/MeCN (minimum volume) to give the title compound. UPLC-MS (Condition 2) tR=1.09 min, m/z=477.0/479.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.62-1.76 (m, 2H) 1.98-2.11 (m, 2H) 3.48-3.60 (m, 2H) 3.70-3.82 (m, 2H) 5.37-5.49 (m, 1H) 7.38 (d, J=9.16 Hz, 2H) 7.88 (d, J=9.00 Hz, 2H) 8.50 (d, J=2.38 Hz, 1H) 8.83 (d, J=2.51 Hz, 1H) 9.16 (s, 2H) 9.23 (s, 1H) 10.45 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:12](I)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([OH:14])[CH:3]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C>O1CCCC1.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>[F:1][C:2]1[C:12]([C:16]#[C:15][C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH:26][C:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=3)(=[O:24])=[O:25])=[CH:21][CH:22]=2)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([OH:14])[CH:3]=1
Reactant: C#Cc1ccc(S(=O)(=O)Nc2ncccc2C)cc1
Reactant: CCOC(=O)c1cc(I)c(F)cc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)c(F)cc1O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Ethyl 4-fluoro-2-hydroxy-5-iodobenzoate (3.6 g, 80%, 10 mmol), 4-ethynyl-N-(3-methyl-2-pyridinyl)benzenesulfonamide (2.7 g, 10 mmol) and triethylamine (5 g, 50 mmol) were suspended in tetrahydrofuran (20 ml) and the mixture heated to 50 ° C. Dichlorobis(triphenylphosphine)palladium (45 mg, 0.06 mmol) and copper(I)iodide (76 mg, 0.4 mmol) were added with stirring. After about 15 min a practically clear solution had formed. After 3 h at 50° C. the solution was taken to dryness and triturated with isobutylmethylketone and dilute hydrochloric acid. The organic phase was separated and the solvent evaporated. The oily residue was triturated with a small amount of acetonitrile to form crystals. These were recrystallized from acetic acid. The product was dissolved in a small amount of chloroform and the solution applied on top of a short silica gel column and eluted with 25% isobutylmethylketone in toluene. The pure product resulted after evaporation of the solvent. Yield 2.0 g, 44 %.
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.CCCCCC.COC1C=CC=CC=1[C@H](N[C@H](C1C=CC=CC=1)C)C1C2C(=CC=CC=2)C=CC=1O.[Br:41][C:42]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][C:43]=1[CH:44]=[O:45].Cl>C1(C)C=CC=CC=1>[Br:41][C:42]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][C:43]=1[C@H:44]([OH:45])[CH2:4][CH3:5]
Reactant: CC[Zn]CC
Reactant: O=Cc1cc(F)ccc1Br
Agent: COc1ccccc1[C@H](N[C@@H](C)c1ccccc1)c1c(O)ccc2ccccc12
Agent: Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC[C@@H](O)c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
With reference to Chirality, 2005, 17, 476-480, 1.06 M solution of diethyl zinc in hexane (18.6 ml, 19.7 mmol) was added dropwise under ice cooling to a solution of 1-[(S)-(2-methoxy phenyl){[(1S)-1-phenylethyl]amino}methyl]-2-naphthol (0.38 g, 0.99 mmol) in toluene (5 ml). The mixture was stirred at room temperature for 1 hour. After stirring, the mixture was added with 2-bromo-5-fluorobenzaldehyde (2.0 g, 9.85 mmol) under ice cooling and stirred at room temperature for 16 hours. The reaction solution was added with 1N aqueous hydrochloride solution and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to give the title compound as a transparent oily substance (1.81 g, yield 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[NH:8]2)=[CH:4][CH:3]=1.O[Li].O.Cl>C1COCC1.CO.O.O>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1cc2ccc(C)cc2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2cc(CCC(=O)O)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of 46 (0.69 g, 3.17 mmol) in THF:MeOH:H2O (1:1:1) (9 mL) was added LiOH.H2O (0.25 g, 5.96 mmol). The reaction was stirred at rt for 16 h, diluted with water, acidified to pH 3 with 1 N HCl, and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over MgSO4, and concentrated in vacuo to provide 0.58 g (90%) of product 47 as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.35 (s, 3H), 2.65 (t, J=8 Hz, 2H), 2.93 (t, J=8 Hz, 2H), 6.05 (s, 1H), 6.75 (d, J=8 Hz, 1H), 7.04 (s, 1H), 7.27 (d, J=8 Hz, 1H), 10.74 (brs, 1H), 12.19 (brs, 1H). LC-MS (CI): m/z 202.0 [(M−H)− C12H13NO2 requires 203.09].