Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:7]([N:8]([CH3:15])[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[C:6]([I:16])[N:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[C:26]#[N:27])=[C:20]([Cl:33])[CH:19]=1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:33][C:20]1[CH:19]=[C:18]([NH:17][C:2]2[C:7]([N:8]([CH3:15])[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[C:6]([I:16])[N:5]=[CH:4][N:3]=2)[CH:32]=[CH:31][C:21]=1[O:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:25]([C:26]#[N:27])[CH:24]=1
Reactant: CN(C(=O)C(F)(F)F)c1c(I)ncnc1I
Reactant: N#Cc1cccc(Oc2ccc(N)cc2Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(C(=O)C(F)(F)F)c1c(I)ncnc1Nc1ccc(Oc2cccc(C#N)c2)c(Cl)c1
Temperature: 100 °C
Yield: 44.3 %

Procedure:
N-(4,6-Diiodopyrimidin-5-yl)-2,2,2-trifluoro-N-methylacetamide (3 g) and 3-(4-amino-2-chlorophenoxy)benzonitrile (1.69 g) were dissolved in 1-methyl-2-pyrrolidone (11.4 mL), and the mixture was stirred with heating at 100° C. for 16 hrs. To the reaction mixture was added aqueous sodium hydrogen carbonate (80 mL) and the mixture was extracted with ethyl acetate (100 mL×2). The organic layer washed with saturated brine (80 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→hexane:ethyl acetate=50:50) and crystallized from diisopropyl ether to give the title compound (1.67 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH:28]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29]1>C1COCC1>[O:24]=[C:23]1[NH:22][N:21]=[C:20]([CH2:25][CH2:26][CH3:27])/[C:19]/1=[C:11]1/[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:32]([CH:28]4[CH2:31][CH2:30][CH2:29]4)=[O:33])=[CH:7][CH:6]=3)=[CH:10]/1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(Cl)C1CCC1
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)C3CCC3)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and cyclobutanecarbonyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.68 (t, J=7.33 Hz, 3H) 1.30 (qd, J=7.49, 7.33 Hz, 2H) 1.78-1.89 (m, 1H) 1.91-2.03 (m, 1H) 2.12-2.16 (m, 2H) 2.18-2.27 (m, 5H) 6.73 (s, 1H) 7.60-7.70 (m, 3H) 7.83-7.94 (m, 4H) 8.14 (d, J=8.08 Hz, 1H) 10.11 (s, 1H); ESI-MS: m/z calc'd for C26H26N4O2S 458.58. found 459.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1.[Cl:31][CH2:32][C:33](Cl)=[O:34]>CC#N>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)[C:33](=[O:34])[CH2:32][Cl:31])=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1
Reactant: O=C(Cl)CCl
Reactant: CCCCCNc1nc(N)nc(C)c1CCCNCc1cccc(CC(=O)OC)c1
Solvent: CC#N
Product: CCCCCNc1nc(N)nc(C)c1CCCN(Cc1cccc(CC(=O)OC)c1)C(=O)CCl
Reaction time: 16 h

Procedure:
The product from Example 1 (0.1 g) was dissolved in MeCN (10 mL) and chloroacetyl chloride (0.027 g) was added. The reaction mixture was stirred for 16 h and the solvents evaporated to give the subtitle compound which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]([O:17]CC)=[O:16].[OH-].[K+]>C(O)C.O>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C=CC=Cc1ccc(OC)c(C)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C=CC=CC(=O)O)c(C)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
A solution of ethyl 5-(2,3-dimethyl-4-methoxyphenyl)-2,4-pentadienoate (2 g, 7.7 mmol) in 10 mL of ethanol was stirred at room temperature under nitrogen and a solution of KOH (1 g) in 2 mL of water was added dropwise. The mixture was stirred at room temperature for 18 hrs. and concentrated in vacuo. The residue was diluted with water and extracted several times with ethyl ether. The aqueous layer was acidified to pH 3 with a 10N HCl solution. The resulting yellow precipitate was extracted into ethyl acetate. The organic solution was washed with brine and dried (Na2SO4). Evaporation in vacuo afforded a yellow powder. Crystallization from ethyl acetate/ethyl ether gave 1.1 g of yellow crystals: MS (CI): 233 (M+1)+, 215.
Reaction SMILES: [OH:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:23])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.N1C=CN=C1.[C:29]([Si:33]([CH3:36])([CH3:35])Cl)([CH3:32])([CH3:31])[CH3:30]>CN(C=O)C.CCOC(C)=O>[Si:33]([O:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:23])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:36])[CH3:35]
Reactant: C[C@]12CC[C@@H]3c4cc([N+](=O)[O-])c(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc2c(cc1[N+](=O)[O-])[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 3-hydroxy-2-nitroestra-1,3,5(10)-trien-17-one (76b, 1.10 g, 3.5 mmol) in DMF (10 mL) were added imidazole (0.476 g, 7.0 mmol) and tert-butyldimethylchlorosilane (0.690 g, 4.6 mmol) at room temperature. The reaction mixture was stirred for 1 h, and diluted with EtOAc, and washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:EtOAc (5:1→2:1, v/v) to afford 1.45 g of 89 (97% yield) mp: 184-185° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]([CH3:14])([CH3:13])[CH2:9][C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.[N:23]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>CN(C=O)C>[NH2:23][C:10](=[O:11])[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)(CC(=O)O)CC(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CC(N)=O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
5-Tert-butoxy-3,3-dimethyl-5-oxopentanoic acid (6 g, 27.8 mmol) was dissolved in DMF (111 mL) and benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (21.68 g, 41.7 mmol), 1-hydroxybenzotriazole (5.6 g, 41.7 mmol), diisopropylethylamine (19.3 mL, 111 mmol) and ammonium chloride (3 g, 55.6 mmol) were added. The mixture was stirred at room temperature for two hours. The DMF was removed under reduced pressure and the residue dissolved in ethyl acetate. The ethyl acetate was washed with 1N KHSO4, saturated sodium bicarbonate, brine, dried (Na2SO4) and concentrated. The residue was again dissolved in ethyl acetate, washed with 0.1N HCl, 0.1N NaOH, H2O, dried (Na2SO4), passed through a pad of silica and concentrated to give 4.9 g (82%) of the desired product. 1H NMR (DMSO-d6) 7.19 (br s, 1H), 6.71 (br s, 1H), 2.23 (s, 2H), 2.08 (s, 2H), 1.4 (s, 9H), 1.02 (s, 6H).
Reaction SMILES: [CH:1]1([C:4]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[CH:7]=[C:6]3[O:22][CH2:23][CH2:24][N:25]([CH2:26][CH:27]([OH:31])[CH2:28][O:29][CH3:30])[C:5]=23)[CH2:3][CH2:2]1.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1O.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[CH:7]=[C:6]3[O:22][CH2:23][CH2:24][N:25]([CH2:26][CH:27]([O:31][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[F:32])[CH2:28][O:29][CH3:30])[C:5]=23)[CH2:2][CH2:3]1
Reactant: Oc1ccccc1F
Reactant: COCC(O)CN1CCOc2cc3c(c(C4CC4)c21)CCN(C(=O)OC(C)(C)C)CC3
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COCC(CN1CCOc2cc3c(c(C4CC4)c21)CCN(C(=O)OC(C)(C)C)CC3)Oc1ccccc1F
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of 300 mg of t-butyl 5-cyclopropyl-4-(2-hydroxy-3-methoxypropyl)-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate in 3 ml of toluene were added 0.1 ml of o-fluorophenol and 250 mg of cyanomethylenetributylphosphorane, followed by stirring at 80° C. for 20 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 277 mg of t-butyl 5-cyclopropyl-4-[2-(2-fluorophenoxy)-3-methoxypropyl]-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate as a pale yellow viscous substance.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C@@H:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:6]([OH:18])[CH2:5]1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])O.[Na+]>C(O)C>[C:12]1([CH2:11][NH:10][C@@H:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:5][C@H:6]2[OH:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ncccn1
Reactant: NCCN1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O[C@@H]1CN(CCNc2ncccn2)CC[C@H]1NCc1ccccc1
Reaction time: 8 h
Yield: 80.3 %

Procedure:
To a stirred solution of 11.2 parts of trans-1-(2-aminoethyl)-4-[(phenylmethyl)amino]-3-piperidinol in 135 parts of ethanol were added 5.7 parts of 2-chloropyrimidine. After the addition of 8.4 parts of sodium hydrogen carbonate, stirring was continued overnight at reflux temperature. After evaporation, the residue was taken up in a mixture of dichloromethane and water. The separated organic layer was washed with water, dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 11.84 parts (80.3%) of trans-4-[(phenylmethyl)amino]-1-[2-(2-pyrimidinylamino)ethyl]-3-piperidinol; mp. 126.9° C. (interm. 18).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[NH:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:9]=1)(=[O:3])[CH3:2].[CH2:25]([O:32][CH2:33][C:34](C)=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][C:33]1([CH3:34])[O:24][C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH:9]=[C:4]2[C:1](=[O:3])[CH2:2]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Reactant: CC(=O)COCc1ccccc1
Product: CC1(OCc2ccccc2)CC(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2O1

Procedure:
The product of Example 4 Step A and 1-(benzyloxy)acetone were combined in a procedure similar to Example 4 Step B to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH:24]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([C:34](O)=[O:35])[C:28]=2[CH:27]=[CH:26][N:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:29]3[C:28]4[CH:27]=[CH:26][N:25]=[CH:24][C:33]=4[CH:32]=[CH:31][CH:30]=3)=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cccc2cnccc12
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4cnccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with isoquinoline-5-carboxylic acid. LC-MS (basic): tR=0.74 min; [M+H]+=488.1.
Reaction SMILES: C([O:4][C:5]([CH3:22])([CH3:21])[CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:12]([O-])=[CH:11][C:10]=2[N:9]=[CH:8]1)(=O)C.CN(C)C=O.P(Cl)(Cl)([Cl:30])=O>ClCCl>[Cl:30][C:11]1[C:10]2[N:9]=[CH:8][N:7]([CH2:6][C:5]([OH:4])([CH3:22])[CH3:21])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)OC(C)(C)Cn1cnc2c[n+]([O-])c3ccccc3c21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cnc2c(Cl)nc3ccccc3c21
Reaction time: 1 h

Procedure:
To a stirred solution of 1.5 g of crude 1-(2-acetoxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-5-oxide from Part C in 10 ml of dichloromethane and 2 ml of N,N-dimethylformamide was added 0.843 g (0.0055 mole) of phosphorus oxychloride. After stirring for one hour, the mixture was evaporated to dryness. Hydrochloric acid was added to the residue, then the mixture was basified with ammonium hydroxide. The product was separated by filtration, washed with water and dried. Recrystallization from ethanol of a portion of the product provided 4-chloro-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline, m.p. 196°-199° C. Analysis: Calculated for C14H14ClN3O: %C, 61.0; %H, 5.2; %N, 15.2; Found: %C, 60.9; %H, 5.3; %N, 15.1.
Reaction SMILES: [N:1]1([C:7]2[C:12]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][O:17][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[ClH:31].[N:1]1([C:7]2[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][O:17][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2cccc(N3CCOCC3)c2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(c(N3CCOCC3)c1)CNCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A mixture of tert-butyl 6-(morpholin-4-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (120 mg, 0.359 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (77.4 mg, 92.0%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.Br[CH2:17][CH:18]1[CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:11][C:10](=[O:12])[N:9]([CH2:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)[C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1CN(Cc2ccc(Br)cc2)C(=O)N1
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN(Cc2ccc(Br)cc2)C(=O)N1CC1CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.6 %

Procedure:
i)—To a solution of 1-(4-bromo-benzyl)imidazolidine-2,4-dione (Example 4, step iii) (5.91 g, 21.96 mmol) in DMF (50 ml) were added (bromomethyl)cyclobutane (6.55 g, 43.9 mmol) and potassium carbonate (9.11 g, 65.9 mmol) under a nitrogen atmosphere. After stirring for 20 h at room temperature, the reaction mixture was concentrated under reduced pressure. The product was extracted in ethyl acetate and the combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give 1-(4-bromo-benzyl)-3-cyclobutylmethyl-imidazolidine-2,4-dione (5.30 g).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]([CH3:23])[CH:21]=O)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>[Pd].CO>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH:20]([CH3:23])[CH2:21][N:4]2[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]2)=[CH:17][CH:18]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C=O)=Cc1ccc(C(C)(C)C)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: [Pd]
Solvent: CO
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN1C[C@@H](C)O[C@@H](C)C1
Yield: 94 %

Procedure:
A mixture of 2,500 parts by volume of methanol, 366 parts of cis-2,6-dimethylmorpholine, 606 parts of 3-p-tertiary butylphenyl-2-methyl-prop-2-enal and 35 parts of catalyst, comprising 0.5% by weight of Pd, 5% by weight of Pr2O3, 1% by weight of Mn, remainder Al2O3, is hydrogenated stepwise, in a stirred autoclave of 5,000 parts by volume capacity, first at 50° C. under 50 bar hydrogen pressure, then at 90° C. under the same pressure and finally at 120° C. under the same pressure, until no further hydrogen is absorbed. The autoclave is then allowed to cool, the catalyst is filtered off and the filtrate is purified by distillation. 856 parts of N-(3'-p-tertiary butylphenyl-2'-methyl-propyl)-cis-2,6-dimethylmorpholine, boiling point 206° C./24 mbar, are obtained. This corresponds to a yield of 94% of theory (based on 3-p-tertiary butylphenyl-2-methyl-prop-2-enal).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].O.C(=O)(O)[O-].[Na+].[CH:25]1([C:28](O)=O)[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][NH:3][C:4]2[S:5][CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:27][CH2:26]1
Reactant: CCOC(=O)c1csc(N)c1C(=O)OCC
Reactant: O=C(O)C1CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1csc(NCC2CC2)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium borohydride (12.5 g) was added portionwise over 3 hours to a stirred solution of diethyl 2-aminothiophene-3,4-dicarboxyate (Example 36a, 25 g) in cyclopropane carboxylic acid (125 ml). The mixture was stirred at room temperature for 18 hours then further sodium borohydride (5 g) was added and stirring was continued at 50° C. for 16 hours. Further sodium borohydride (5 g) was again added and stirring was continued at 50° C. for 16 hours and then at room temperature for 3 days. Water (500 ml) was added, the mixture was neutralised with sodium bicarbonate and extracted with ether (2×250 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography over silica, eluting with ether/isohexane (2:3) to give the subtitle compound (12.10 g) as an oil.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([CH3:33])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[N:17]=[N:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:32])[CH3:6])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:33][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[N:17]=[N:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:32])([CH3:6])[C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nn2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nn2)ccc1OC(C)(C)C(=O)O

Procedure:
0.183 g (0.386 mmol) of the above prepared 2-methyl-2-{2-methyl-4-[6-(4-trifluoromethyl-phenyl)-pyridazin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester was dissolved in 8 ml of THF/EtOH=1/1, treated with 1.16 ml (3 eq.) of 1N NaOH and kept at ambient temperature over night. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase extracted again with AcOEt; the combined organic layers were washed with water, dried over sodium sulfate, and evaporated to dryness to yield, after recrystallisation from hexane/AcOEt, 0.160 g of the title compound as light yellow crystals of mp. 191–192° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]([CH3:25])[CH3:24].C(O)(=O)C(O)=O>CO.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)CBr
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CC(C)CN1CCC(O)(c2cc(F)cc(F)c2)C1

Procedure:
Preparation according to Example 51. Enantiomer E1 of 3-(3,5-difluorophenyl)-pyrrolidin-3-ol (0.18 g, 0.92 mmol), acetonitrile (6 mL), potassium carbonate (0.25 g, 1.84 mmol), 1-bromo-2-methylpropane (0.1 mL, 0.92 mmol). Flash chromatography on silica gel (ethyl acetate/methanol, 9:1). Yield: 0.18 g. [α]D=+22.6° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diisopropyl ether: M.p. 164-165° C.; MS m/z (relative intensity, 70 eV) 255 (M+, 2), 212 (bp), 182 (46), 213 (12), 127 (8), 98 (6) 1-bromo-2-methylpropane.
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O[CH:24](OCC)[CH2:25][NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])C.Cl>CO.O>[CH2:30]([O:29][C:27]([NH:26][CH2:25][CH:24]1[C:13]2[NH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]=2[CH2:11][CH2:10][N:9]1[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: c1ccc(CNCCc2c[nH]c3ccccc23)cc1
Reactant: CCOC(CNC(=O)OCc1ccccc1)OCC
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C(NCC1c2[nH]c3ccccc3c2CCN1Cc1ccccc1)OCc1ccccc1
Yield: 62 %

Procedure:
To a solution of 50 g of N-benzyl-tryptamine hydrochloride (i.e., 3-(2-(benzylamino)-ethyl)indole hydrochloride) in 500 ml of methanol-water (4:1) are added 57.9 g of N-benzyloxycarbonyl-aminoacetaldehyde diethylacetal and 25 ml of 10% hydrochloric acid, and the mixture is refluxed for 16 hours. After the reaction, the reaction mixture is evaporated under reduced pressure to remove solvent, and the resultant crystals are collected by filtration. After being washed with water and ether, said crystals are added to a saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove solvent. The residue (oil, 60 g) is purified by silica gel chromatography (Solvent: chloroform-methanol (20:1)). 46 g of 1,2,3,4-tetrahydro-1-((N-benzyloxycarbonylamino)methyl)-2-benzyl-β-carboline are thereby obtained as a caramel. Yield: 62%
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.Cl.C(OC1C2C(=CC=CC=2)CC[N:17]=1)C.[Cl-].[NH4+].C(=O)([O-])[O-].[Na+].[Na+].NN>C(O)C>[NH:1]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1)[NH2:17]
Reactant: NC1=NCCc2ccccc21
Reactant: CCOC1=NCCc2ccccc21
Agent: Cl
Agent: NN
Agent: O=C([O-])[O-]
Solvent: CCO
Product: NNC1=NCCc2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 1-amino-3,4-dihydroisoquinoline (VI: R=R'=Y=Y'=Z=Z'=H) hydrochloride (m.p. 133°-134° C., 0.5 g.), prepared from 1-ethoxy-3,4-dihydroisoquinoline and ammonium chloride, sodium carbonate (0.38 g.), hydrazine (0.41 g.) and ethanol (15 ml.) was stirred (at 25° C.). The mixture was filtered. An ether solution of the crystals which separated from the filtrate on chilling was washed with water, dried and filtered. Concentration of the filtrate and crystallization of the residue from ether afforded 1-hydrazino-3,4-dihydroisoquinoline (0.44 g.).