Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:25][N:13]2[CH2:14][CH2:15][N:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[CH2:17][CH:12]2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>Cl.C(O)C.[Pd]>[O:1]([CH2:8][CH:9]1[CH2:25][N:13]2[CH2:14][CH2:15][N:16]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)[CH2:17][CH:12]2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nccc(N2CCN3CC(COc4ccccc4)CCC3C2)n1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(OCC2CCC3CN(c4ccncn4)CCN3C2)cc1
Yield: 20.1 %

Procedure:
A mixture of 0.110 g (0.307 mmol) of (7RS,9aSR)-7-phenoxymethyl-2-(2-chloropyrimidin4-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Example 29), 20 mg of 10% Pd/C, and several drops of conc. hydrochloric acid in 30 mL of ethanol were shaken under 50 psi of hydrogen gas at room temperature for 6 h. The mixture was filtered through Celite and the filtrate was evaportated. The residue was basified with conc. ammonium hydroxide, extracted with chloroform, dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with a solvent gradient from 100% chloroform to 95:5 chloroform:methanol gave 0.020 g (20%) of the title compound. mp (.HCl) >265° C. (dec). HRMS calc for C19H24N4O: 324.1945, found: 324.1970.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl[C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[C:14]1([C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[S:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1ccc(S)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C(O)Cc1ccc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 2 h
Yield: 86.9 %

Procedure:
4-mercaptophenylacetic acid (369.6 mg, 2.2 mmol) was added to the solution of chlorotriphenylmethane (557.6 mg, 2 mmol) in 2.0 mL of anhydrous dichloromethane. The solution was stirred for 2 hrs under nitrogen. The reaction was quenched by 1N NaOH (3 mL). The suspension was extracted with 10 mL of ethyl acetate, and the organic phase was washed with brine (5 mL×3) and dried over anhydrous magnesium sulfate. The solvent was removed and residue was purified by flash chromatography on silica gel (eluent: ethyl acetate/hexane=⅓) to afford 713.4 mg of desired product (87%). 1H NMR (400 MHz, CDCl3) δ 7.43-7.40 (m, 6H), 7.26-7.17 (m, 9H), 6.93 (m, 4H), 3.52 (s, 2H) ESI-MS: observed [M+Na]+: 433.6, calculated: 410.5.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].C(O[C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]3[NH:36][C:37]4[N:53]=[C:41]([NH:42][C:43]5[CH:44]=[CH:45][CH:46]=[C:47]([CH:52]=5)[CH2:48][CH2:49][C:50]=2[CH:51]=3)[N:40]=[CH:39][C:38]=4[Cl:54])=[O:30])[CH2:24][CH2:23]1)=[O:21])(C)(C)C.[CH3:55][C:56]1[O:60][N:59]=[C:58](C(Cl)=O)[CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:54][C:38]1[CH:39]=[N:40][C:41]2[NH:42][C:43]3[CH:44]=[CH:45][CH:46]=[C:47]([CH:52]=3)[CH2:48][CH2:49][C:50]3[CH:51]=[C:35]([NH:36][C:37]=1[N:53]=2)[CH:34]=[CH:33][C:32]=3[NH:31][C:29](=[O:30])[CH2:28][N:25]1[CH2:26][CH2:27][N:22]([C:20]([C:58]2[CH:57]=[C:56]([CH3:55])[O:60][N:59]=2)=[O:21])[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCN(CC(=O)Nc3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 56 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using tert-butyl-4-(2-[{6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)piperazine-1-carboxylate bis(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as starting materials in 56% yield. LCMS for C29H30ClN8O3 (M+H)+: m/z=573.2.
Reaction SMILES: C([NH:5][C:6]1[S:7][CH2:8][C:9]2([N:35]=1)[C:22]1[CH:21]=[C:20]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:18][C:17]=1[O:16][C:15]1[C:10]2=[CH:11][C:12]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)=[CH:13][CH:14]=1)(C)(C)C.Br>>[CH2:24]([O:23][C:20]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)=[CH:13][CH:14]=3)[C@@:9]3([CH2:8][S:7][C:6]([NH2:5])=[N:35]3)[C:22]=2[CH:21]=1)[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)COc1ccc2c(c1)C1(CSC(NC(C)(C)C)=N1)c1cc(-c3cncnc3)ccc1O2
Agent: Br
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(CSC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A resealable tube charged with a solution of N-tert-butyl-2′-(neopentyloxy)-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine (0.033 g, 0.068 mmol) in 48% HBr (1.00 mL, 18.42 mmol) was heated to 80° C. After 3 hrs, the solution was cooled and evaporated to dryness with a stream of N2. The residue was treated with CH2Cl2 (2 mL) and TEA (0.1 mL). The solution was loaded onto a silica gel column and purified with 1-5% MeOH:CH2Cl2 w/1% NH4OH(Rf=0.5 in 10% MeOH:CH2Cl2 w/1% NH4OH) to afford racemic material that was resolved by chiral chromatography to give both (R) and (S)-2′-(neopentyloxy)-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine. MS Found: MH+=433.2.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].[C:18]1([CH2:24][CH2:25]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[C:3]([NH:6][C:7]([CH2:25][CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4]
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccccc1)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (50.6 g) in dimethylformamide (1500 ml) was dropwise added a solution of diethyl acetamidomalonate (250 g) in dimethylforamide (200 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 2-Phenylethyl bromide (156 ml) was dropwise added thereto and the resultant mixture was stirred for 7 hours at room temperature. The reaction mixture was poured into ice water (1500 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled away. The obtained residue was crystallized from toluene to give the title compound (102 g) as white crystals, melting point 115-117° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:25])=O>ClCCl>[Cl:25][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: OCc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Fc1ccc(Oc2ccc(CCl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To the solution of (4-(4-fluorophenoxy)phenyl)methanol (7 g, 32.1 mmol) and pyridine (5.19 mL, 64.2 mmol) in dichloromethane (DCM) (100 mL) was added sulfurous dichloride (7.63 g, 64.2 mmol) dropwise at 0° C. After addition the mixture was stirred at room temperature overnight. The mixture was washed with saturated NaHCO3 solution (40 mL×2) and brine (40 mL), the organic phase was dried over Na2SO4, filtered and concentrated to leave the crude product, which was purified by column chromatography (silica-gel, elution with PE: EtOAc=6:1) to afford the pure 1-(chloromethyl)-4-(4-fluorophenoxy)benzene (2.2 g, 8.83 mmol, 27.5% yield) as light yellow oil. LCMS: rt=1.56 min, [M+H+]=237
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:8][CH2:9][NH:10][C:11]1[N:16]2[N:17]=[C:18]([CH3:21])[C:19](I)=[C:15]2[N:14]=[C:13]([CH3:22])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6](=[O:28])[N:7]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:8][CH2:9][NH:10][C:11]1[N:16]2[N:17]=[C:18]([CH3:21])[C:19]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:29])[C:35]=3[Cl:36])=[C:15]2[N:14]=[C:13]([CH3:22])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCCC2)n2nc(C)c(I)c2n1
Reactant: OB(O)c1cccc(Cl)c1Cl
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: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCCC2)n2nc(C)c(-c3cccc(Cl)c3Cl)c2n1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 60 %

Procedure:
A suspension of cyclopentyl-[2-(3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino)-ethyl]-carbamic acid tert-butyl ester (38 mg, 0.076 mmol) and 2,3-dichlorobenzeneboronic acid in toluene (0.5 mL)/ethanol (0.5 mL)/2 M aqueous sodium carbonate (0.22 mL) was degassed (3×) by alternately pulling a vacuum followed by repressurization with nitrogen. Tetrakis(triphenylphosphine)palladium (10 mg, 0.009 mmol) was added, and the mixture was degassed (3×) again. The mixture was stirred for 2.5 hours at 100° C., concentrated under reduced pressure, and then chromatographed (4:1 hexanes/ethyl acetate) to give the product as colorless oil (24 mg, 60%): +APcI MS (M+1)+ 518; 1H NMR (CDCl3) δ7.42 (dd, 1 H), 7.30 (dd, 1H), 7.22 (t, 1H), 5.84 (s, 1H ), 4.25-4.10 (br s, 1H), 3.49 (s, 4H), 2.44 (s, 3H), 2.32 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: CCOCC.[N:6]([O-])=O.[Na+].[NH:10]([C:12]1[N:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:15]=[CH:14][C:13]=1[C:25]#[N:26])[NH2:11].Cl>O>[N:10]([C:12]1[N:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:15]=[CH:14][C:13]=1[C:25]#[N:26])=[N+:11]=[N-:6]
Reactant: O=N[O-]
Reactant: N#Cc1cnn(-c2ccc(Cl)cc2Cl)c1NN
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N#Cc1cnn(-c2ccc(Cl)cc2Cl)c1N=[N+]=[N-]
Yield: 43 %

Procedure:
10 ml of ether and then 0.85 g (0.012 mol) of sodium nitrite in 10 ml of water are added to 2.7 g (0.01 mol) of 5-hydrazino-4-cyano-1-(2,4-dichlorophenyl)-pyrazole in a solution of 1.9 ml of concentrated hydrochloric acid in 10 ml of water at 0° C. When the addition has ended, a further 20 ml of water and 30 ml of ether are added, the mixture is filtered, the ether phase is separated off, dried over calcium chloride and concentrated in vacuo and the oil thus obtainable is purified by chromatography (silica gel; mobile phase: methylene chloride/acetone 9:1). 1.2 g (43% of theory) of 5-azido-4-cyano-1-(2,4-dichlorophenyl)-pyrazole are obtained as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:26][CH:25]=1)[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:22][CH3:23])=[CH:29][CH:28]=1)[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CCc1ccc(NCCN2CCCCC2)cc1
Product: CCc1ccc(N(CCN2CCCCC2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 111.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.72 g) and (4-ethylphenyl) (2-piperidinoethyl)amine (0.50 g) as starting materials, 5-benzyloxy-N-(4-ethylphenyl)-N-(2-piperidinoethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.19 g) was obtained. By the reaction and treatment in the same manner as in Example 105 using this compound, N-(4-ethylphenyl)-5-hydroxy-N-(2-piperidinoethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.77 g) was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[C:28]([C:30]1[CH:31]=[C:32]([CH:40]([CH2:44][CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[C:41](O)=[O:42])[CH:33]=[CH:34][C:35]=1[S:36]([CH3:39])(=[O:38])=[O:37])#[N:29].[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=1>C(Cl)Cl>[C:28]([C:30]1[CH:31]=[C:32]([CH:40]([CH2:44][CH:45]2[CH2:46][CH2:47][CH2:48][CH2:49]2)[C:41]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)=[O:42])[CH:33]=[CH:34][C:35]=1[S:36]([CH3:39])(=[O:38])=[O:37])#[N:29]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
A solution of triphenylphosphine (98 mg, 0.37 mmol) in methylene chloride (1 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (67 mg, 0.37 mmol). The reaction mixture was stirred at 0° C. for 15 min and then treated with 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 75, 100 mg, 0.31mmol). The resulting reaction mixture was stirred at 0° C. for. 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminopyridine (64 mg, 0.68 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (94.5 mg, 76%) as a yellow foam: mp 87-90° C. (foam-to gel); EI-HRMS m/e calcd for C21H23N3O3S (M+) 397.1460, found 397.1460.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[CH:15]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12]
Reactant: O=C1Cc2cc(F)c(Cl)cc2N1
Reactant: O=Cc1cccc(Cl)c1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)c(F)cc2/C1=C/c1cccc(Cl)c1

Procedure:
In a manner similar to the method described in example 1a, 6-chloro-5-fluoro-1,3-dihydro-indol-2-one (0.25 g, 1.35 mmol, prepared in procedure described in EP153818) was reacted with 3-chloro-benzaldehyde (0.34 g, 2.44 mmol) and pyrrolidine (0.19 g, 2.68 mmol) in methanol to give a mixture of E- and Z-6-chloro-3-(3-chloro-benzylidene)-5-fluoro-1,3-dihydro-indol-2-one as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.O>CS(C)=O>[C:1]1([C:7]2([O:13][C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Clc1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(C2(Oc3cnccn3)CCNCC2)cc1
Temperature: 25 °C
Yield: 3.9 %

Procedure:
A mixture of 4-phenyl-4-piperidinol (7.1 g, 40 mM), DMSO (50 ml) and sodium hydride (2 g of a 50% dispersion in oil) was heated at 80° until homogenous, cooled to room temperature and treated with chloropyrazine (4.6 g, 40 mM) in DMSO (10 ml). After 24 hours the reaction mixture was poured on to water (250 ml) and extracted with toluene (2×250 ml). The combined organic phases were washed with brine, dried and the solvents removed under reduced pressure. Sublimation of the residue at 0.1 mm Hg (bath temp. 100°) gave the title compound (400 mg) m.p. 107°-8°.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)(=[O:20])[CH3:19]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CO)C2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1Cc2cc(C)c3[nH]c(=O)ccc3c2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a solution of 2-hydroxymethyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (261 mg) in anhydrous pyridine (7 ml), acetic anhydride (233 mg) was added. The mixture was stirred at room temperature for 1 hour, and further stirred at 50° C. for 1 hour. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in chloroform, and washed with water. After drying, the solvent was distilled off to obtain 305 mg of a crude product. The crude product was purified by silica gel column chromatography (eluent=chloroform:methanol=70:1) to obtain 247 mg of a target product (80.0%). The product was recrystallized from chloroform-n-hexane, and as a result, colorless powdery crystals were obtained (mp. 197°-200° C.).
Reaction SMILES: [C:1]([C:3]1[C:4]([I:25])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:6][C:7]=1[NH:8]CC1C=CC(OC)=CC=1OC)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:7]1[S:6][C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([I:25])[C:3]=1[C:1]#[N:2]
Reactant: CCOC(=O)c1sc(NCc2ccc(OC)cc2OC)c(C#N)c1I
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1sc(N)c(C#N)c1I
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
To a solution of ethyl 4-cyano-5-[(2,4-dimethoxybenzyl)amino]-3-iodothiophene-2-carboxylate (4.50 g, 9.53 mmol) in dichloromethane (100 mL) at room temperature was added trifluoroacetic acid (22.5 mL, 292 mmol). The mixture was then stirred at room temperature for 10 minutes. The solvent was evaporated and the excess trifluoroacetic acid was removed by azeotroping with toluene. The crude material was diluted with ethyl acetate, then treated with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate five times and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield ethyl 5-amino-4-cyano-3-iodothiophene-2-carboxylate (2.85 g, 88%). LCMS: (FA) ES+, 323. 1H NMR (400 MHz, d6-DMSO) δ: 8.18 (s, 2H), 4.20-4.16 (m, 2H), 2.50-2.48 (m, 3H). To a suspension of 5-amino-4-cyano-3-iodothiophene-2-carboxylate (2.85 g, 8.85 mmol) in acetonitrile (46.2 mL) under argon was added diiodomethane (2.49 mL, 31.0 mmol). The mixture was heated to 38° C. for 30 minutes, then amyl nitrite (2.59 g, 22.1 mmol) was added dropwise over 5 minutes. The reaction was slowly allowed to cool to room temperature then the mixture was concentrated and column chromatography was performed to yield the title compound (3.20 g, 79%). LCMS: (FA) ES+, 434. 1H NMR (400 MHz, d6-DMSO) δ: 4.33-4.27 (m, 2H), 2.51-2.47 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([Cl:35])[C:33]=1[OH:34])[C:5]([NH:7][CH:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([NH:19][CH:20]([CH:25]=[O:26])[CH2:21][C:22]([OH:24])=[O:23])=[O:18])[N:12]([CH2:27]CC)[C:11](=[O:30])[CH2:10][CH2:9]1)=[O:6].C(Br)C=C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([Cl:35])[C:33]=1[OH:34])[C:5]([NH:7][CH:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([NH:19][CH:20]([CH:25]=[O:26])[CH2:21][C:22]([OH:24])=[O:23])=[O:18])[N:12]([CH3:27])[C:11](=[O:30])[CH2:10][CH2:9]1)=[O:6]
Reactant: CCCN1C(=O)CCC(NC(=O)c2cc(Cl)c(O)c(Cl)c2)C(=O)N1CC(=O)NC(C=O)CC(=O)O
Solvent: C=CCBr
Product: CN1C(=O)CCC(NC(=O)c2cc(Cl)c(O)c(Cl)c2)C(=O)N1CC(=O)NC(C=O)CC(=O)O

Procedure:
3-{2-[6-(3,5-Dichloro-4-hydroxy-benzoylamino)-3,7-dioxo-2-methyl-[1,2]diazepan-1-yl]-acetylamino}-4-oxo-butyric acid (11d) was prepared according to the method used to prepare (11c) only substituting iodomethane for allyl bromide.
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[Cl:18][C:19]1[N:24]=[C:23]([C:25](=O)[CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][CH:20]=1>C(O)C>[Cl:18][C:19]1[N:24]=[C:23]([C:25]2[C:26]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[CH:29][CH:28]=3)=[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][N:3]3[N:2]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cc1ccnc2ccccc12)c1cccc(Cl)n1
Reactant: N[n+]1ccccc1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Clc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Temperature: 110 °C
Yield: 18.8 %

Procedure:
Add 1-aminopyridinium iodide (780 mg, 3.53 mmol), N,N-diisopropylethylamine (0.62 mL, 3.53 mmol), 1-(6-chloro-pyridin-2-yl)-2-quinolin-4-yl-ethanone (500 mg, 1.77 mmol), and ethanol (8 mL) to a sealed tube apparatus. The sealed vessel is heated at 110° C. for 5 hours. After cooling, the crude is concentrated in vacuo. Purification by flash column chromatography (Silica Gel, 25-40% acetone/hexanes) provides the title compound 119 mg (19%) as an orange solid.
Reaction SMILES: CO.[OH:3][C:4]1([CH3:18])[CH2:9][CH:8]([OH:10])[CH2:7][C:6]([CH3:12])([CH3:11])[CH:5]1[CH:13]=[CH:14][C:15](=[O:17])[CH3:16].[BH4-].[Na+]>C(O)(=O)C>[OH:3][C:4]1([CH3:18])[CH2:9][CH:8]([OH:10])[CH2:7][C:6]([CH3:11])([CH3:12])[CH:5]1[CH:13]=[CH:14][CH:15]([OH:17])[CH3:16]
Reactant: CC(=O)C=CC1C(C)(C)CC(O)CC1(C)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(O)C=CC1C(C)(C)CC(O)CC1(C)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 320.1 %

Procedure:
To 20 ml of a methanol solution containing 200 mg of 4-(2,4-dihydroxy-2,6,6-trimethylcyclohexyl)but-3-en-2-one was added 40 mg of sodium borohydride under ice-cooling, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was treated with acetic acid, and the solvent, etc. were removed by distillation under reduced pressure. Ethyl acetate was added to the residue, followed by washing with a saturated sodium chloride aqueous solution and then, with water. The organic layer was dried over magnesium sulfate, and the ethyl acetate was removed by distillation. The residue was purified by silica gel column chromatography to obtain 646 mg (yield: 73%) of 4-(2,4-dihydroxy-2,6,6-trimethylcyclohexyl)but-3-en-2-ol.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[CH:18]([NH:20][C:21]1[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH2:31])[CH:27]=3)[N:22]=1)[CH2:17][CH2:16][CH2:15]2>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[CH:18]([NH:20][C:21]1[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH:31][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH:27]=3)[N:22]=1)[CH2:17][CH2:16][CH2:15]2
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2
Product: COc1cccc2c1C(Nc1ccc3cc(NS(=O)(=O)N(C)C)ccc3n1)CCC2

Procedure:
The title compound was prepared in accordance with the general method described in example 66 from dimethylsulfamoyl chloride and rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-diamine; MS: m/e=427.3 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.P(Cl)(Cl)(Cl)=O.CN([CH:18]=[O:19])C>>[CH:18]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:19]
Reactant: CN(C)C=O
Reactant: c1ccc2[nH]ccc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccccc12

Procedure:
As shown by the above generalized scheme, the indole is treated with phosphorus oxychloride and DMF to produce the corresponding 3-formyl indole (XIV). The latter is treated with nitromethane and ammonium acetate to obtain the corresponding 3-(2'-nitroethenyl)indole (XV), which then is reduced to the desired tryptamine (XVI).