Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](O)([C@@H:4]([CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:30])[CH2:20][C@@H:21]2O)=[CH:16][CH:15]=3)[CH2:12][CH2:11]1)[CH3:9])C)[CH3:3].[N+]([O-])([O-])=O.[K+]>CCOCC>[CH3:23][C:22]1[CH2:21][CH2:20][C@H:19]([OH:30])[CH2:18][C:17]=1/[CH:16]=[CH:15]\[C:14]1[C@@H:13]2[CH2:12][CH2:11][C@H:10]([C@@H:8]([CH2:7][CH2:6][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:9])[C@@:27]2([CH3:28])[CH2:26][CH2:25][CH:24]=1
Reactant: C[C@H](CC[C@@H](C)C(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC1=C(/C=C\C2=CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]23)C[C@@H](O)CC1
Yield: 28.3 %

Procedure:
(24R)-5,7-Ergostadiene-1α,3β,25-triol (IIb) (100 mg, 0.23 mmol) prepared in Example 13 was dissolved in ether (1000 ml) and the solution was irradiated for 3 minutes with high pressure mercury lamp using 1.5% aqueous potassium nitrate solution as a filter under water-cooling in an argon gas stream. From the reaction solution was distilled off ether and the resultant residue was purified by preparative high performance liquid chromatography (HPLC) [column: LiChrosorb® Si60 (7 μm), φ25×250 mm, Merck Co., Ltd.; column effluent: 6% methanol-methylene chloride; flow rate: 6.0 ml/ml, detected at 265 nm] to give 25.0 mg of previtamin D (XIIb).
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[C:24]1([C@H:30]([NH2:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([C@H:30]([NH:38][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:22])[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N[C@H](Cc1ccccc1)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)N[C@H](Cc1ccccc1)c1ccccc1
Yield: 80 %

Procedure:
The title compound was prepared in a yield of 80% in a similar manner to that described in Example 1 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and (R)-1,2-diphenylethylamine.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=4[O:24][CH3:25])=[N:11][C:10]=3[N:9]([CH3:26])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@@H:47]1[CH2:51][CH2:50][O:49][CH2:48]1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.O1CCCC1>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C@H:47]5[CH2:51][CH2:50][O:49][CH2:48]5)=[CH:19][C:18]=4[O:24][CH3:25])=[N:11][C:10]=3[N:9]([CH3:26])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O[C@@H]1CCOC1
Reactant: COc1cc(O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(O[C@H]2CCOC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a 10 ml tetrahydrofuran suspension of 150 ml (0.423 mmol) of the compound obtained in Example 36, 133 mg (0.508 mmol) of triphenylphosphine, 51 μl (0.635 mmol) of (R)-(−)-3-hydroxytetrahydrofuran, and 80 μl (0.508 mmol) of diethyl azodicarboxylate were slowly added at room temperature, and the mixture was stirred at room temperature for 1 hour. Further, 44 mg (0.169 mmol) of triphenylphosphine, 17 μl (0.212 mmol) of (R)-(−)-3-hydroxytetrahydrofuran, and 27 μl (0.169 mmol) of diethyl azodicarboxylate were added, and the mixture was stirred at room temperature for 1.5 hours. Then, the reaction mixture was diluted with ethyl acetate, and the dilution was washed with water and a saturated aqueous solution of sodium chloride in this order. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1˜1/2) to obtain 124 mg (69%) of the captioned compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH2:35]([N:37]1[CH2:42][CH2:41][N:40]([CH2:43][C:44]#[CH:45])[CH2:39][CH2:38]1)[CH3:36]>>[CH2:35]([N:37]1[CH2:42][CH2:41][N:40]([CH2:43][C:44]#[C:45][C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([N:19]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[C:20]([C:22]4([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]4)=[O:21])=[CH:3][C:2]=3[F:1])[CH:15]=2)[CH2:39][CH2:38]1)[CH3:36]
Reactant: C#CCN1CCN(CC)CC1
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Product: CCN1CCN(CC#Cc2cc3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c3s2)CC1
Yield: 9.6 %

Procedure:
Prepared from N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 50 mg, 0.0845 mmol) and 1-ethyl-4-(prop-2-ynyl)piperazine (Example 18, Step A, 32.2 mg, 0.211 mmol) using the procedure described for Example 6, Step B. The crude was purified by preparative TLC (1 mm thickness, Rf=0.67), eluting with 10% MeOH (containing 7N NH3) in CHCl3. The product was obtained as a waxy solid (5 mg, 10%). HPLC: 100% purity (220 nm); LRMS (APCI−): 100% purity, 220 nm, m/z 614 (M−1) detected; 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.49 (d, J=5 Hz, 1H), 8.31 (br s, 1H), 7.75 (m, 1H), 7.58 (s, 1H), 7.43 (m, 2H), 7.24 (m, 2H), 7.06 (m, 2H), 6.52 (d, J=5 Hz, 1H), 3.64 (m, 2H), 3.61 (s, 2H), 2.4-2.8 (m, 8H), 1.80 (m, 2H), 1.62 (m, 2H), 1.12 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:26])[CH2:16][CH:17]([O:24][CH3:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:26])[CH2:16][CH:17]([O:24][CH3:25])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: COC(CC(C)Nc1c(C)noc1-c1ccc(Br)cc1)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CC(OC)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(3-methoxy-1-methyl-3-phenyl-propyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[F:11][C:12]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:4]1[N:3]([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:12]=3[F:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: O=C(O)Cn1nccn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2F)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2F)CN1C(=O)Cn1nccn1
Yield: 63 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride and (2S,4R)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 52, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (77 mg, 63%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.00 (s, 1H), 7.80 (s, 2H), 7.60-7.52 (m, 2H), 7.47-7.36 (m, 1H), 7.29-7.14 (m, 4H), 7.11-6.92 (m, 6H), 5.49 (q, 2H), 4.54-4.46 (m, 1H), 3.92-3.80 (m, 1H), 2.86-2.63 (m, 3H), 2.20-1.88 (m, 2H). MS (EI) for C28H24F3N5O3. found 535.9 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN1CCCC1=O>[C:13]1([NH:12][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)Cc1ccccc1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(O)Cc1ccccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-bromophenylacetic acid (25 mmol) was added to a mixture of 50 mmol of aniline, 50 mmol of anhydrous potassium carbonate, (7%) mmol of activated copper powder, and 3 ml of N-methylpyrrolidone at 120° C. The mixture was kept at 120° C. for 4 h with stirring. The resulting slightly grayish mixture was filtered while hot through a bed of Celite and the Celite was washed with water (200 ml) and hexane (200 ml). The filtrate was transferred to a separating funnel and extracted with hexane and cooled to room temperature. The aqueous layer was removed, cooled to 5° C., and neutralized with dilute hydrochloric acid (1:3) which was also kept at 5° C. The precipitated 2-[(phenyl)amino]phenylacetic acid was collected by filtration, thoroughly washed with water, and dried under suction.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:19]=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)=[CH:24][CH:25]=1
Reactant: ClCCN1CCOCC1
Reactant: O=C(c1ccc2[nH]ccc2c1)N1CCC(Oc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc2c(ccn2CCN2CCOCC2)c1)N1CCC(Oc2ccc(Cl)cc2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
To a stirred solution of (4-(4-chlorophenoxy)piperidin-1-yl)(1H-indol-5-yl)methanone (30 mg, 0.085 mmol, Step-1) and sodium hydride (60% in oil, 6 mg, 0.25 mmol) in N,N-dimethylformamide (1.5 mL) was added 4-(2-chloroethyl)morpholine hydrochloride (35 mg, 0.19 mmol) at room temperature. Then the mixture was stirred at 70° C. for 2 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with water (20 mL), and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica-gel column chromatography (NH-gel, eluting with ethyl acetate) and then preparative LC-MS to give 11.9 mg (30% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:13])=[O:12].[CH2:14]1[O:16][CH2:15]1>>[OH:16][CH2:15][CH2:14][S:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)O)c1
Reactant: C1CO1
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)CCO)c1

Procedure:
A process for the preparation of the sulphone of the formula ##STR3## wherein 2-chloro-5-nitrobenzenesulphochloride is reacted with sodium sulphite to give 2-chloro-5-nitrobenzenesulphinic acid, the benzenesulphinic acid product is then reacted with ethylene oxide to give 2-chloro-5-nitrophenyl hydroxyethyl sulphone and the latter is then treated with hydrogen in the presence of hydrogenation catalysts to form the sulphone.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[CH2:22]([NH2:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[CH2:22]([NH:40][C:16](=[O:18])[CH:15]([C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=1)[CH3:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Reactant: CCCCCCCCCCCCCCCCCCN
Product: CCCCCCCCCCCCCCCCCCNC(=O)C(C)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and stearylamine were used to obtain N-Stearyl-3,4-dihydroxyphenylpropionamide by carrying out the same procedures as described in Example 1.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:23]CC5C=CC=CC=5)[CH:17]=4)[NH:12][C:11]=3[C:10]([O:31][CH2:32][CH3:33])=[CH:9][C:8]=2[C:6]1=[O:7].[H][H]>C(O)(=O)C.[C].[Pd]>[CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([OH:23])[CH:17]=4)[NH:12][C:11]=3[C:10]([O:31][CH2:32][CH3:33])=[CH:9][C:8]=2[C:6]1=[O:7]
Reactant: [H][H]
Reactant: CCOc1cc2c(c3c1[nH]c1ccc(OCc4ccccc4)cc13)C(=O)N(CCN(C)C)C2=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOc1cc2c(c3c1[nH]c1ccc(O)cc13)C(=O)N(CCN(C)C)C2=O
Yield: 80.3 %

Procedure:
In 10 ml of acetic acid was dissolved 31 mg of N-(2-dimethylaminoethyl)-6-benzyloxy-1-ethoxycarbazole-3,4-dicarboximide. Thereto was added 30 mg of 5% palladium-carbon. The mixture was subjected to catalytic reduction in a hydrogen atmosphere at room temperature at atmospheric pressure. The resulting insoluble material was removed by filtration. The filtrate was subjected to distillation under reduced pressure to remove the solvent. The residue was mixed with 50 ml of ethyl acetate and 50 ml of an aqueous saturated sodium hydrogencarbonate solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous potassium carbonate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethanol to obtain 20 mg (yield: 80%) of N-(2-dimethylaminoethyl)-1-ethoxy-6-hydroxycarbazole-3,4-dicarboximide as orange crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][C:5](=[O:9])[C:6](O)=[O:7].C(Cl)(=O)C([Cl:14])=O>>[CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][C:5](=[O:9])[C:6]([Cl:14])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)CCC(=O)C(=O)O
Product: CC(C)CCC(=O)C(=O)Cl

Procedure:
reacting 5-methyl-2-oxohexanoic acid with at least a 10% excess of the stoichiometric amount of oxalyl chloride under anhydrous conditions at a temperature of 25° to 60° C. for from 40 to 60 hours to form 5-methyl-2-oxohexanoyl chloride;
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]([NH2:35])[CH2:27][O:26]1>>[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]([NH:35][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:27][O:26]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1COCc2ccccc21
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2COCc3ccccc32)cn1
Yield: 96 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using rac-3,4-dihydro-1H-isochromen-4-amine hydrochloride instead of methylamine, to the title compound (136 mg, 96%) which was obtained as an off white solid. MS: m/e=442.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.[H-].[Na+].I[CH:21]([CH3:23])[CH3:22]>CN(C)C=O>[CH:21]([O:17][C:4]1[CH:5]=[CH:6][C:7]([B:8]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]2)=[C:2]([CH3:1])[CH:3]=1)([CH3:23])[CH3:22]
Reactant: CC(C)I
Reactant: Cc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OC(C)C)ccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
In a flame-dried flask under nitrogen, 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (see WO2007092751A, 2.30 g, 9.82 mmol) was dissolved in dimethylformamide (40 mL). Sodium hydride 60% dispersion in mineral oil (0.48 g, 12 mmol) was added to the mixture. The reaction mixture was stirred at room temperature under nitrogen for 30 minutes. 2-Iodopropane (2.55 g, 15.00 mmol) was added and the reaction mixture was stirred at 70° C. for 18 hours. The reaction mixture was quenched with water. The organics were extracted 3 times with diethylether. The organic layers were combined, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography, using as eluant a mixture of heptane/ethyl acetate, to afford 2.02 g (73% yield) of 2-(4-isopropoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as a yellow oil. MS m/z 277 [MH]+
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[NH2:25])[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[Cl:27][CH2:28][C:29](=N)OCC.C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCCl>[Si:1]([O:8][CH2:9][C@@H:10]([N:14]1[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=[C:29]1[CH2:28][Cl:27])[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOC(=N)CCl
Reactant: CC(C)[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c(N)cnc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)[C@@H](CO[Si](C)(C)C(C)(C)C)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 70 °C
Yield: 82.9 %

Procedure:
N4-[(1S)-1-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-methylpropyl]quinoline-3,4-diamine (5.05 g, 14.0 mmol) was dissolved in 140 mL of dry 1,2-dichloroethane and the solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (3.33 g, 21.1 mmol) was then added and the reaction mixture was heated to 70° C. After stirring for 2 days, the reaction mixture was cooled and treated with 70 mL of CHCl3 and 100 mL of saturated sodium bicarbonate (NaHCO3) solution. The layers were separated and the organic portion was washed with H2O and brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 33%-50% ethyl acetate/hexanes) gave 1-[(1S)-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylpropyl]-2-(chloromethyl)-1H-imidazo[4,5-c]quinoline (4.85 g) as a dull yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([CH3:29])[N:21]=2)=[CH:16][CH:15]=1.Cl>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]4)=[CH:4][CH:3]=3)=[O:25])=[C:22]([CH3:29])[N:21]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc2ccc(N)cc2n1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Agent: Cl
Product: Cc1ccc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)nc3C)cc2n1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-amino-2-methylquinoline (D66) (20 mg, 0.13 mmol) and 6-(4-fluorophenyl)-2-methylnicotinic acid (D24) (30 mg, 0.13 mmol) then converted to the HCl salt as a beige solid by treatment with ethereal HCl. 1H NMR (400 MHz, DMSO) (HCl salt) δ (ppm): 11.39 (br.s, 1H), 9.04 (s, 1H), 8.96 (d, 1H), 8.30 (d, 1H), 8.23 (dd, 2H), 8.12 (d, 1H), 8.00 (m, 2H), 7.84 (d, 1H), 7.37 (t, 2H), 2.94 (s, 3H), 2.71 (s, 3H)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].[CH3:41]NCC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:39]([S:36]([N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:15]4[CH:14]=[C:13]([CH2:12][N:10]([CH3:11])[CH2:8][CH2:9][CH3:41])[S:17][CH:16]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:31][CH2:32]1)(=[O:37])=[O:38])[CH3:40]
Reactant: CCNC
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 32.4 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting methyl(propyl)amine (73 mg, 1.0 mmol) for N-methylethanamine to afford 20.0 mg of the title compound (32.4%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][C:19]=2[CH3:20])[NH:16][C:15]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH:44]([CH3:46])[CH3:45])(=O)=O>>[CH:44]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][CH:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]3)=[C:19]([CH3:20])[CH:18]=2)[CH:14]=[C:15]1[C:21]([N:23]1[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:27][CH2:28]1)=[O:22])([CH3:46])[CH3:45]
Reactant: CC(C)OS(C)(=O)=O
Reactant: Cc1cc2[nH]c(C(=O)N3CCN(S(C)(=O)=O)CC3)cc2cc1OC1CCN(C(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc2c(cc1OC1CCN(C(C)C)CC1)cc(C(=O)N1CCN(S(C)(=O)=O)CC1)n2C(C)C
Yield: 9 %

Procedure:
The title compound was synthesized in analogy to example 4, from [5-(1-isopropyl-piperidin-4-yloxy)-6-methyl-1H-indol-2-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone (example 29), cesium carbonate and isopropyl methanesulfonate, to afford the title compound as a light-yellow oil (9%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([CH3:30])[CH:24]=1>C(#N)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][C:26]1[CH:28]=[CH:29][C:23]([OH:22])=[CH:24][C:25]=1[CH3:30])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Reactant: Cc1cc(O)ccc1N
Solvent: CC#N
Product: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccc(O)cc1C
Yield: 44.8 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(2-methylthioethoxy)quinoline (2.48 g, 6.63 mmol) and 4-hydroxy-2-methylaniline (1.06 g, 8.62 mmol) in acetonitrile (20 ml) was refluxed for 8 h. The reaction mixture was evaporated and the residue was chromatographed (SiO2 ; CH2Cl2 :MeOH 95:5) yielding 1.22 g (45%) of the desired product.