Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[CH3:22][SnH:23]([CH3:25])[CH3:24]>>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([S:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Sn:23]([CH3:25])([CH3:24])[CH3:22])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: C[SnH](C)C
Reactant: C=CCCCCCCCCCS(=O)(=O)c1ccc(C)cc1
Product: Cc1ccc(S(=O)(=O)CCCCCCCCCCC[Sn](C)(C)C)cc1

Procedure:
The procedure described in Example 5 was employed except that 13.1 g (42.5 mmoles) of 10-undecenyl-p-tolyl sulfone and 14.0 g (85 mmoles) of trimethyltin hydride were the reactants. The reaction mixture was irradiated for 189 hours. The excess trimethyltin hydride was allowed to evaporate from the reaction mixture under a flow of nitrogen. The residual oil weighed 15.5 g. One-half of the crude product was chromatographed on a column containing silica gel using toluene and 2% acetone in toluene as eluents. The product, 11-(p-tolylsulfonyl)undecyltrimethylstannane, was obtained as an oil. The presence of both the sulfonyl and trimethyltin groups was indicated by the strong infrared absorption bands at 1315 cm-1, 1300 cm-1, 1285 cm-1, 1140 cm-1 (--SO2 --) and 760 cm-1 [(CH3)3Sn--]. NMR showed the following:
Reaction SMILES: [Li].N.Cl.[NH:4]1[C:12]2[C:7](=[C:8]([C:13]3(O)[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.O1CCCC1>C(O)C>[NH:15]1[CH2:16][CH2:17][CH2:18][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:7]=2[CH:6]=[CH:5][NH:4]3)[CH2:14]1
Reactant: OC1(c2cccc3[nH]ccc23)CCCNC1
Agent: Cl
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCO
Product: c1cc(C2CCCNC2)c2cc[nH]c2c1
Yield: 69.9 %

Procedure:
700 mg of lithium were added in small fractions over one hour at -40° C. to a mixture of 100 ml of ammonia, 1.2 g of 3-(1H-indol-4-yl)-3-piperidinol hydrochloride, 20 ml of tetrahydrofuran and 10 ml of anhydrous ethanol and the ammonia was evaporated at room temperature. The residue was taken up in 100 ml of water and the aqueous phase was extracted with chloroform containing 10% methanol. The organic phase was washed with water, dried and filtered. The filtrate was evaporated to dryness and the 950 mg of residue was chromatographed over silica gel. Elution with a 7-2-1-chloroform-methanol-triethylamine mixture yielded 665 mg of 4-(piperidin-3-yl)-1H-indole.
Reaction SMILES: [CH2:1]([CH:8]([C:22]([OH:24])=[O:23])[C:9](O)([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([C:8]1[C:22]([O:24][C:10](=[O:12])[C:9]=1[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(Cc1ccccc1)C(O)(CCc1ccccc1)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1OC(=O)C(Cc2ccccc2)=C1CCc1ccccc1
Temperature: 115 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To the crude 3-benzyl-2-hydroxy-2-phenethylsuccinic acid obtained was added acetic anhydride (2.5 mL), and the mixture was stirred at 115° C. for 3 h. The acetic anhydride was evaporated under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 10:1) to give 180 mg of the title compound as a solid (2 step yield: 81%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:26])[CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]3[CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]3[N:27]=[CH:28][CH:29]=[CH:30][C:9]=3[NH:8][C:7](=[O:31])[C:6]=2[CH:32]=1.[C:33](#N)C>>[CH2:24]([N:21]([CH2:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][N:14]1[CH2:13][C:12]([N:11]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:32][C:6]=2[C:7](=[O:31])[NH:8][C:9]2[CH:30]=[CH:29][C:28]([CH3:33])=[N:27][C:10]1=2)=[O:26])[CH2:22][CH3:23])[CH3:25]
Reactant: CCN(CC)CC1CCCCN1CC(=O)N1c2ccc(Cl)cc2C(=O)Nc2cccnc21
Reactant: CC#N
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2ccc(C)nc21

Procedure:
8-Chloro-11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one of m.p. 186° to 188° C. (acetonitrile using active charcoal);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]3[CH2:19][O:18]3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[N-:20]=[N+:21]=[N-:22].[Na+].[NH4+].[Cl-].O>CCO>[N:20]([CH2:19][CH:17]([OH:18])[CH2:16][N:6]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)=[N+:21]=[N-:22]
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NCC(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21

Procedure:
3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (500 mg, 1.3 mmol), NaN3 (111 mg, 1.7 mmol), NH4Cl (91 mg, 1.7 mmol), were combined in 4 ml of EtOH and 1 ml of H2O and heated to 80° C. overnight. Upon completion, the EtOH was evaporated and the mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine and dried over Na2SO4 and concentrated. The material was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[N:21]O)[NH2:20])=[CH:17][CH:16]=1.O>C1C=CC=CC=1>[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]2[N:21]=[C:7]([C:3]3[O:4][CH:5]=[CH:6][C:2]=3[CH3:1])[O:9][N:20]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccoc1C(=O)O
Reactant: NC(=NO)c1ccc(Cl)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1ccoc1-c1nc(-c2ccc(Cl)cc2)no1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
A solution of 3-methyl-furan-2-carboxylic acid (252 mg, 2 mmol), thionyl chloride (0.5 mL) in benzene (5 mL) was stirred at 60° C. for 8 h and evaporated to dryness. The residue was dissolved in pyridine (10 mL), and to the solution was added 4-chloro-benzamidoxime (340 mg, 2 mmol). The solution was refluxed for 10 h and then cooled to room temperature. The solution was diluted by water (20 mL) to produce a precipitate. The solid was collected by filtration and washed with water, then dried to yield 201 mg (39%) of the title compound. 1H NMR (CDCl3): 8.12 (d, J=8.4 Hz, 2H), 7.62 (d, J=1.5 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H), 6.50 (d, J=1.5 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])=[O:9].C1(C)C=CC=CC=1.[CH2:29]([O:31][SiH:32]([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])[CH3:30]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Si:32]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])[O:31][CH2:29][CH3:30])=[O:9]
Reactant: C=CCCCCOC(=O)C=Cc1ccc(OC)c(OC)c1
Reactant: CCO[SiH](OCC)OCC
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCO[Si](CCCCCCOC(=O)C=Cc1ccc(OC)c(OC)c1)(OCC)OCC
Temperature: 25 °C

Procedure:
A mixture of 0.50 g of hex-5-enyl 3,4-dimethoxycinnamate, 1.0 ml of toluene, 2.9 ml of triethoxysilane and 0.02 ml of a solution of 134 mg of hexachloro(IV) platinic acid hexahydrate in 10 ml of isopropanol is allowed to react overnight at 40° C. The reaction mixture is then cooled to room temperature and filtered over a silica gel pad and the filtrate is completely evaporated down. Chromatography of the residue over silica gel gives 6-triethoxysilanylhexyl 3,4-dimethoxycinnamate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]([OH:11])[C:8]([CH3:13])([CH3:12])[C:7]=2[CH:14]=1)#[N:2].[CH2:15](N(CC)CC)[CH3:16].O.C(OCC)C>C(O)C.S(=O)(=O)(O)O>[CH3:13][C:8]1([CH3:12])[C:7]2[CH:14]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:10][CH:9]1[O:11][CH2:15][CH3:16]
Reactant: CCN(CC)CC
Reactant: CC1(C)c2cc(C#N)ccc2OC1O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CCOC1Oc2ccc(C#N)cc2C1(C)C

Procedure:
The product of stage (b) (32.2 g) was boiled under reflux in ethanol (200 ml) containing sulphuric acid (7 drops) for 2 hours. The solution was cooled, neutralised with triethylamine and reduced to half volume under vacuum. Addition to water and isolation through diethyl ether gave 34.4 g of crude title product as a yellow oil. This was dissolved in petroleum ether bp 40°-60° C. containing 5% diethyl ether, then filtered through a bed of aluminium oxide followed by elution with the same solvent mixture. This yielded 30.5 g of the pure product as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11](I)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:15]([C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C>C1COCC1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11]([C:16]#[C:15][C:17]3[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:29][CH:30]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cnc(I)cn2)cc1
Reactant: C#Cc1ccc(OCCN2CCCC2)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1ccc(-c2cnc(C#Cc3ccc(OCCN4CCCC4)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an N2 atmosphere 19 mg (0.1 mmol) CuI, 82 mg (0.1 mmol) [1,1′-bis-(diphenylphosphine)-ferrocene]-palladium(II)-chloride are added to a solution of 316 mg (1.0 mmol) 2-(4-chloro-phenyl)-5-iodo-pyrazine and 215 mg (1.0 mmol) 1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine in 50 mL THF and 0.4 mL (3 mmol) triethylamine and the reaction mixture is stirred overnight at RT. To complete the reaction another 100 mg (0.32 mmol) 2-(4-chloro-phenyl)-5-iodo-pyrazine are added and the mixture is again stirred overnight. It is evaporated down i. vac., the residue is combined with 10% Na2CO3 solution, extracted exhaustively with DCM, the combined organic phases are washed three times with water and dried over MgSO4. This is filtered through activated charcoal, evaporated down i.vac. and the residue is purified by chromatography (silica gel, gradient: EtOAc to EtOAc/MeOH/NH3 9:9:1).
Reaction SMILES: [I:1][C:2]1[C:21]([C:22]([O:24]CC)=[O:23])=[C:5]2[CH2:6][N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]([C:10]([F:13])([F:12])[F:11])[CH2:9][N:4]2[N:3]=1.[OH-].[Na+]>C(O)C.O>[C:17]([O:16][C:14]([N:7]1[CH:8]([C:10]([F:11])([F:12])[F:13])[CH2:9][N:4]2[N:3]=[C:2]([I:1])[C:21]([C:22]([OH:24])=[O:23])=[C:5]2[CH2:6]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)c1c(I)nn2c1CN(C(=O)OC(C)(C)C)C(C(F)(F)F)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2c(C(=O)O)c(I)nn2CC1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
To a solution of Intermediate 346D (0.22 g, 0.450 mmol) in ethanol (2 mL) and water (2 mL) was added NaOH (0.036 g, 0.899 mmol) and the solution was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and the pH of the crude product was adjusted to 2 with an aqueous solution of 1.5N HCl and extracted with EtOAc (2×20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate concentrated under reduced pressure to afford Intermediate 346E as a white solid (0.12 g, 55%). MS(ES): m/z=462.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.4 (br, s., 1H), 5.55-5.38 (m, 1H), 5.18-5.08 (m, 1H), 4.54 (m, 3H), 1.48 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([C:18]([F:19])([F:20])[F:21])=[N:13]3)=[CH:4][C:3]=1[C:34]1[CH:35]=[N:30][CH:31]=[N:32][CH:33]=1
Reactant: O=S(=O)(Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F)C(F)(F)F
Reactant: OB(O)c1cncnc1
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1-c1cncnc1
Yield: 40.9 %

Procedure:
Trifluoromethanesulfonic acid 2-fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenyl ester (30.0 mg, 0.068 mmol) was coupled to 5-pyrimidinylboronic acid (prepared as described in WO 9411372; 11.0 mg, 0.089 mmol) as described in Example 35 part c), affording 5-(4-fluoro-3-pyrimidin-5-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (10.3 mg, 41%). δH (360 MHz, CDCl3) 7.49 (1H, t, J 9.5), 7.55-7.61 (3H, m), 7.86 (1H, d, J 8.4), 8.51 (1H, d, J 8.4), 9.01 (2H, d, J 1.1), 9.28 (1H, s), 9.32 (1H, d, J 4.6). m/z (ES+) 371 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH2:18][O:19]COC)=[CH:17][C:12]=3[C:11]3=[N:23][CH:24]=[N:25][N:10]3[C:9]2=[O:26])=[CH:5][CH:4]=1.Cl>CO>[OH:19][CH2:18][C:16]1[CH:15]=[N:14][C:13]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[C:9](=[O:26])[N:10]3[N:25]=[CH:24][N:23]=[C:11]3[C:12]=2[CH:17]=1
Reactant: COCOCc1cnc2c(c1)c1ncnn1c(=O)n2Cc1ccc(OC)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(CO)cnc32)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
A suspension of 6-(4-methoxybenzyl)-9-((methoxymethoxy)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (Example 31, 40 mg, 0.10 mmol), methanol (0.80 mL) and 5 N hydrochloric acid (0.40 mL) was stirred at 50° C. for 16 h. The mixture was extracted with DCM (1 mL), basified to pH 14 with 15% aqueous sodium hydroxide and extracted with DCM (2 mL). The combined DCM extracts were concentrated under reduced pressure. Purification (HPLC, 10-90% ACN-water) afforded the title compound (21 mg, 59%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 3.69 (s, 3H), 4.69 (d, J=4.6 Hz, 2H), 5.54 (t, J=4.6 Hz, 1H), 5.59 (s, 2H), 6.84 (d, J=6.9 Hz, 2H), 7.36 (d, J=6.9 Hz, 2H), 8.58 (d, J=1.6 Hz, 1H), 8.60 (s, 1H), 8.72 (d, J=1.6 Hz, 1H). [M+H]=338.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][C@H:7]1[CH2:19][OH:20])=[O:5])[CH3:2].C(N(CC)CC)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14])[CH2:8][C@H:7]1[CH2:19][O:20][S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=1)(=[O:36])=[O:35])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a cold (0° C.) solution of (1R,2R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxymethyl-cyclopentanecarboxylic acid ethyl ester (example 68 step 4, 500 mg) and triethyl amine (836 mg) in dichloromethane (5 mL) was added toluene-4-sulfonyl chloride (1.53 g). The reaction mixture was stirred overnight at room temperature then partitioned between hydrochloric acid (1N) and dichloromethane. The aqueous layers was extracted with dichloromethane and the combined organic layers were washed with half saturated aqueous solution of sodium hydrogenocarbonate and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of cyclohexane/ethyl acetate (1:0 to 19:1 v/v) as eluant to afford the title compound (602 mg, 80%) as a yellow liquid.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:27]([N:3]1[CH2:2][CH2:1][C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: COC(=O)C1CNCCc2c1[nH]c1ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CCN1CCc2c([nH]c3ccccc23)C(C(=O)OC)C1
Yield: 83 %

Procedure:
A 72 L three-necked mechanically stirred round bottomed flask was set up with a reflux condenser. To the flask was charged dry tetrahydrofuran (10 L), and methyl 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate (800 g, 3.27 mol). The mixture was stirred, and tetrabutylammonium bromide (21.1 g, 0.06 mol), anhydrous potassium carbonate (1.13 kg, 8.8 mol), and allyl bromide (29.7 mL, 396 g, 3.27 mol) were added sequentially in one lot each. After addition, the mixture was stirred at about 20° C. for 2.5 days. The mixture was diluted with (10 L) hexanes, filtered, and transferred to a separatory funnel. The solution was washed with water (2 L), saturated sodium chloride (1 L), dried over sodium sulfate, filtered, then concentrated to a dark green-brown oil (770 g), methyl 3-allyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate, suitably clean to be used in the next synthetic step. Yield=83%. TLC (EtOH/CH2Cl2, 1:9): Rf=0.7; 1H NMR (400 MHz, CDCl3): δ 2.79-2.86 (m, 1H), 2.90-3.09 (m, 4H), 3.28-3.43 (m, 3H), 3.78 (s, 3H), 4.02 (dd, J=1.6, 6.8 Hz, 1H), 5.23 (d, J=10.4 Hz, 1H), 5.27 (dd, J=1.4, 17 Hz, 1H), 5.90-6.00 (m, 1H), 7.11-7.19 (m, 2H), 7.29 (d, J=7.6 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 8.40 (bs, 1H); 13C NMR (100 MHz, CDCl3): δ 24.1, 45.4, 52.2, 55.7, 56.9, 61.4, 110.7, 113.8, 117.5, 118.0, 119.2, 121.4, 128.4, 132.1, 134.7, 135.7, 172.5; melting point: 105-108° C. (uncorrected).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11]C(=O)OC(C)(C)C)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2ncccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of tert-butyl N-(quinolin-6-yl)carbamate (1.3 g, 5.32 mmol) in DCM (40 ml) was added TFA (10 ml) with stirring overnight at room temperature. The resulting mixture was concentrated under vacuum, diluted with water (30 ml), adjusted pH to 8 with NaHCO3 solution, extracted with dichloromethane (2×20 ml), dried over magnesium sulfate and concentrated in vacuo to give quinolin-6-amine as a yellow solid (666 mg, 87%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][C:12]([F:11])([F:21])[F:22])=[CH:15][CH:16]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cccc(Br)n1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)n1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 59.1 using 6-bromopicolinic acid and 4-(trifluoromethoxy)aniline to afford the title compound as a white powder. UPLC-MS (Condition 2) tR=1.27 min, m/z=361.0/363.0 [M+H]+.
Reaction SMILES: [Na:1].OC[O:4][PH:5]([C:7](=[O:14])[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:6].C(O)=[O:16]>>[Na:1].[O:14]=[C:7]([P:5]([OH:4])([OH:6])=[O:16])[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: O=CO
Reactant: COC(=O)CCC(=O)[PH](=O)OCO
Agent: [Na]
Product: COC(=O)CCC(=O)P(=O)(O)O

Procedure:
A solution of the product of Example 9 (5.0 g, 0.0215 mol) in formic acid (50 ml) was refluxed for 21/2 hours. The solution was evaporated in vacuo. Toluene (~25 ml) was added to the residue and was evaporated to dryness. This procedure was repeated twice. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:14][CH2:15][CH2:16][C:17](=O)[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:8][C:7]=1[CH3:27].O=P(Cl)(Cl)Cl.[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>>[CH3:13][O:12][C:10]1[C:9]([S:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:8][C:7]([CH3:27])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:28])=[O:2]
Reactant: COC(=O)COc1cc(OC)c(SCCC(=O)N(C)c2ccccn2)cc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(OCC(=O)O)c(C)cc1SCCCN(C)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Compound 63A was dissolved POCl3 (250 mg, 1.6 mmol) and stirred for 15 minutes. The reaction was concentrated by blowing with nitrogen followed by concentration under vacuum. The intermediate was dissolved in 5 ml dimethoxyethane and cooled to ca. 5 C. Sodium borohydride (20 mg, 0.53 mmol) was added followed by warming to room temp. After 3 h 25 ml 2N HCl was added and heated to boiling for 1 minute. Saturated sodium bicarbonate was added to pH ca. 7-8. The crude product was extracted with 2×20 ml ethyl acetate, dried over anhydrous sodium sulfate, decanted and concentrated. Liquid chromatography gave the title product as a clear colorless oil. MS m/z 391 (M+1). Step 4. Preparation of {5-Methoxy-2-methyl-4-[3-(methyl-pyridin-2-yl-amino)-propylsulfanyl]-phenoxy}-acetic acid (Compound 63)
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[O:6]/[C:5](=[C:7]2/[C:8](=[O:17])[NH:9][C:10]3[C:15]/2=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)/[CH:4]=[C:3]1[C:18]1[CH:19]=[N:20][C:21]([CH:24]=[CH2:25])=[CH:22][CH:23]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.O>CN(C=O)C>[CH3:1][C:2]1([CH3:26])[O:6]/[C:5](=[C:7]2/[C:8](=[O:17])[NH:9][C:10]3[C:15]/2=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)/[CH:4]=[C:3]1[C:18]1[CH:19]=[N:20][C:21]([CH2:24][CH2:25][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:22][CH:23]=1
Reactant: C=Cc1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)ccc43)OC2(C)C)cn1
Reactant: C1COCCN1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(CCN2CCOCC2)nc1
Temperature: 96 °C

Procedure:
A mixture of (3E)-3-[5,5-dimethyl-4-(6-vinylpyridin-3-yl)furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one (50 mg, 0.14 mmol) and morpholine (0.2 mL, 2.3 mmol) in 5 mL of DMF was heated in 96° C. bath under nitrogen for 3 hours. The mixture was cooled to room temperature and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-3-{5,5-dimethyl-4-[6-(2-morpholin-4-ylethyl)pyridin-3-yl]furan-2(5H)-ylidene}-6-fluoro-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 40 mg, 64%.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH:20]=[C:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=4)[NH:13][CH:12]=3)[N:7]([CH3:8])[CH2:6]1)=[O:4].[N:22]#CBr>ClCCl.CO.ClCCl>[CH3:1][O:2][C:3]([C@@H:5]1[CH:20]=[C:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14]([NH:13][CH:12]=3)=[CH:15][CH:16]=[CH:17][C:18]=42)[N:7]([C:8]#[N:22])[CH2:6]1)=[O:4]
Reactant: N#CBr
Reactant: COC(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C#N)C1

Procedure:
To a 50 ml round-bottom flask containing a solution of lysergic acid methyl ester (1.0 g, 3.54 mmol) in anhydrous dichloromethane (50 ml) is slowly added cyanogen bromide (2.02 g, 19.11 mmol) and the resulting black-coloured reaction mixture is stirred at room temperature for 4 hours by which time TLC in 10% methanol/dichloromethane showed partial conversion of starting material to give two faster-running products. The reaction mixture is left stirring over the weekend and monitored by TLC showing no change. The reaction mixture is then stirred at 50° C. for 4 hours and is then extracted between tartaric acid and dichloromethane. The aqueous phase is re-extracted with dichloromethane (100 ml) and the combined organic phases washed with brine (200 ml), dried over MgSO4, filtered and concentrated in vacuo to give a dark brown (tar-coloured) oil. Purification is carried out by Normal Phase Flash column chromatography (Biotage Flash 40, 90 g cartridge) using 40% ethyl acetate/hexane to achieve separation of the fast-running product which is isolated as a pale yellow solid. The product is crystallized from tert. Butyl methylether and slowly evaporated. The resulting crystallized material is filtered at the pump to give pale yellow crystals.