Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH:13]1[CH2:15][CH:14]1[C:16](O)=O.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:32][N:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[N:35][C:34]1=[NH2+:41].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:40][C:36]1[CH:37]=[C:38]([CH3:39])[N:33]2[N:32]=[C:16]([CH:14]3[CH2:15][CH:13]3[C:3]3[N:2]([CH3:1])[CH:6]=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:4]=3)[N:41]=[C:34]2[N:35]=1
Reactant: Cc1cc(C)n(N)c(=[NH2+])n1
Reactant: Cn1cc(-c2ccccc2)nc1C1CC1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)n2nc(C3CC3c3nc(-c4ccccc4)cn3C)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)cyclopropanecarboxylic acid (70 mg, 0.289 mmol) in DMF (2.0 mL) was added 1-amino-4,6-dimethylpyrimidin-2(1H)-iminium 2,4,6-trimethylbenzenesulfonate (98 mg, 0.289 mmol) followed by O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (93 mg, 0.289 mmol) and triethylamine (0.040 mL, 0.289 mmol) at rt. After 2 h stirring at rt, the reaction mixture was stirred at 70° C. for 12 h. The crude product was purified by prep HPLC using Phenomenex column and MeOH—H2O-TFA as eluent (20% to 100% over 12 min gradient; flow: 40 mL/min) Collected the pure fractions and removed solvent. Obtained 5,7-dimethyl-2-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidine as a white solid in 47% yield. Prepared hydrochloride salt by adding 1.0 M HCl and MeOH and removing solvent. 1H NMR (500 MHz, METHANOL-d4) δ 6.28 (s, 1H), 6.18-6.14 (m, 2H), 5.97 (s, 1H), 5.92-5.88 (m, 2H), 5.87-5.84 (m, 1H), 2.39 (s, 3H), 1.72-1.69 (m, 1H), 1.62-1.57 (m, 1H), 1.29-1.27 (m, 3H), 1.17 (s, 3H), 0.70 (dt, J=9.2, 6.1 Hz, 1H), 0.62-0.59 (m, 1H); MS (ESI) 345 (M+H); Rf=1.84 (Condition A).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH:21]=O)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[I-:23].[CH3:24][N+:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH3:35])=[CH:27][CH:26]=1.N1CCCCC1>C(O)C>[I-:23].[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17](/[CH:21]=[CH:35]/[C:28]3[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N+:25]([CH3:24])=[CH:26][CH:27]=3)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: Cc1cc[n+](C)c2ccccc12
Reactant: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Agent: [I-]
Solvent: CCO
Solvent: C1CCNCC1
Product: COCCOCCn1c2ccccc2c2cc(/C=C/c3cc[n+](C)c4ccccc34)ccc21
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution mixture of 3a (0.14 g, 0.5 mmol), 4 (0.18 g, 0.6 mmol) and piperidine (0.1 mL) in ethanol (40 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed. The residue was purified by recrystallization from methanol to afford SLM (0.24 g) as red solid in 56% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.28 (d, J=6.4 Hz, 1H), 9.14 (d, J=8.4 Hz, 1H), 8.86 (s, 1H), 8.51 (d, J=6.4 Hz, 1H), 8.42 (m, 3H), 8.28 (m, 2H), 8.13 (d, J=8.8 Hz, 1H), 8.08 (t, J=7.2 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.32 (t, J=7.2 Hz, 1H), 4.64 (t, J=5.2 Hz, 2H), 4.52 (s, 3H), 3.84 (t, J=5.2 Hz, 2H), 3.48 (m, 2H), 3.33 (m, 2H), 3.11 (s, 3H). 13C NMR (400 MHz, DMSO-d6) δ 153.0, 147, 144.9, 142.1, 140.9, 138.8, 134.9, 129.0, 127.3, 126.7, 126.4, 126.1, 122.8, 122.2, 121.7, 120.4, 119.9, 119.3, 116.2, 115.1, 110.5, 110.4, 71.3, 69.8, 68.9, 58.1, 44.2, 42.9. HRMS (MALDI-TOF) m/z Calcd for C29H29N2O2 437.2223. Found 437.2207 [M+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:2]=1.[CH2:16]([S:20][CH2:21][C:22](O)=[O:23])[CH2:17][CH2:18][CH3:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[C:22](=[O:23])[CH2:21][S:20][CH2:16][CH2:17][CH2:18][CH3:19])[CH:2]=1
Reactant: Clc1ccc(CNc2cccnc2)cc1
Reactant: CCCCSCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCSCC(=O)N(Cc1ccc(Cl)cc1)c1cccnc1

Procedure:
N-(3-pyridyl)-N-[(4-chlorophenyl)methyl]-α-(n-butylthio)acetamide was prepared by reacting 5.0 g. of N-(3-pyridyl)-[(4-chlorophenyl)methyl]amine with 3.5 g. of α-(n-butylthio)acetic acid and 5.0 g. of N,N'-dicyclohexylcarbodiimide in 100 ml. of dichloromethane according to the method of Example 2. Weight collected was 3.9 g as an oil.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]([C:11]2([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[O:10])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:4]1([CH2:7][O:8][C:9]([C:11]2([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=3)[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[O:10])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C#N)cc2)(C(=O)OCC2CCCCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(CC2(C(=O)OCC3CCCCC3)CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-cyano-benzyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-cyclohexylmethyl ester (3.90 mmol; 1.72 g) in dichloromethane (12 mL) at 0° C. was added trifluoroacetic acid (12 mL) and the resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was evaporated. The resulting residue was dissolved in ethyl acetate (50 mL) and washed with a saturated sodium bicarbonate solution (25 mL) and brine (25 mL). The organic phase was dried over magnesium sulfate, filtered, and evaporated to yield 4-(4-cyano-benzyl)-piperidine-4-carboxylic acid cyclohexylmethyl ester. 1H-NMR (CDCl3): 7.55 (1H, d), 7.20 (1H, d), 3.90 (2H, dd), 3.35 (2H, m), 2.70-3.10 (3H, m), 2.60 (1H, m), 2.25 (1H, m), 0.70-2.20 (15H, m).
Reaction SMILES: C(OC(CCCCC(O[C:18]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:20][C:19]=1[C:29]1[CH:34]=[CH:33][C:32](OC(CCCCC(OCC2C=CC=CC=2)=O)=O)=[CH:31][CH:30]=1)=O)=O)C1C=CC=CC=1.[H][H].C1COCC1>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[O:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[CH:18]=[C:19]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(CCCCC(=O)Oc1ccc(-c2oc3ccccc3c(=O)c2OC(=O)CCCCC(=O)OCc2ccccc2)cc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1cc(-c2ccccc2)oc2ccccc12
Yield: 130.9 %

Procedure:
A mixture of 3,4′-di-(benzyloxycarbonylbutylcarbonyloxy)flavone (435 mg, 0.629 mmol) and Pd(OH)2 (50 mg) in EtOAc (5 mL) was treated with hydrogen for 2 h resulting in a grey precipitate. THF was added to dissolve the precipitate and the mixture was filtered (Celite). The pad washed with THF, and the filtrate concentrated. The solid residue was recrystallised from THF/petrol to afford the bis(hemiadipate) as a colourless solid (183 mg, 50%); mp 133° C.; 1H NMR (500 MHz, d6-DMSO) δ 1.55-1.70 (m, 8H, CH2CH2), 2.24 (t, 2H, J=7.0 Hz, CH2CO), 2.27 (t, 2H, J=7.0 Hz, CH2CO), 2.63 (t, 2H, J=7.0 Hz, CH2CO), 2.64 (t, 2H, J=7.0 Hz, CH2CO), 7.37 app. d, 2H, J=9.0 Hz, H3′,5′), 7.55 (dd, 1H, J5,6=8.5, J6,7=7.5, Hz, H6), 7.80 (d, 1H, J7,8=8.5 Hz, H8), 7.88 (ddd, 1H, J6,7=7.5, J7,8=8.5, J5,7=1.5 Hz, H7), 7.96 (app. d, 2H, J=9.0 Hz, H2′,6′), 8.08 (dd, 1H, J5,6=8.5, J5,7=1.5 Hz, H5); 13C NMR (125 MHz, d6-DMS) δ 23.77, 23.82, 32.6, 33.2, 33.3; 44.3 (CH2), 118.7, 122.5, 122.6, 122.7, 125.1, 126.8, 129.7, 132.9, 134.8, 152.7, 154.9, 155.1 (Ar), 170.4, 171.1, 171.4, 174.3, 174.3 (5C, C═O); IR 3059, 2940, 2873, 1768, 1706, 1504, 759 cm−1; HRMS (ESI−) m/z 509.1441, C27H25O10 [M−H]− requires 509.1442.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:32]([N:34](CC)CC)[CH3:33].BrCC#N>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]3[CH2:33][C:32]#[N:34])[CH2:9][CH2:10][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3cccc(Cl)c3)CCC1)NCC2
Agent: N#CCBr
Solvent: ClCCl
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3cccc(Cl)c3)CCC1)N(CC#N)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-[2-({1-[1-(3-Chlorophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}oxy)ethyl]propane-1-sulfonamide (70 mg, 0.14 mmol, cf. example 49) was dissolved in dry dichloromethane (0.5 mL). Triethylamine (35.5 mg, 0.35 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. After addition of 2-bromoacetonitrile (20 mg, 0.168 mmol) stirring at room temperature was continued over night. The reaction mixture was diluted with dichloromethane and washed with aqueous saturated NaHCO3 solution (5 mL) and water (5 mL). The organic phase was dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane then dichloromethane:methanol=200:1). Yield: 35 mg (0.07 mmol, 50%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]3[C:10]=2[NH:9][C:8]2[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]3=2)[CH:27]=[C:28]([CH3:30])[CH:29]=1
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Reactant: Cc1cc(C)cc(B(O)O)c1
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3cc(C)cc(C)c3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 3,5-dimethylphenylboronic acid in step 1.F.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH2:6][CH:5]1[OH:20])=[N+:2]=[N-:3].C(N(CC)CC)C.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([O:20][CH:5]2[CH:4]([N:1]=[N+:2]=[N-:3])[CH2:10][CH2:9][N:8]([C:11]3[N:15]([CH3:16])[N:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])[CH2:7][CH2:6]2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(O)C(N=[N+]=[N-])CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCN(c3c([N+](=O)[O-])cnn3C)CCC2N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.4 %

Procedure:
To a solution of 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol (4.0 g, 14.2 mmol) in dry DCM (100 mL) cooled to 0° C. was added slowly triethylamine (4.0 mL, 28.5 mmol) followed by DMAP (175 mg, 1.42 mmol) and 4-methylbenzene-1-sulfonyl chloride (4.1 g, 21.4 mmol) portionwise. The reaction mixture was allowed to warm to room temperature and stirred for 18 hr. More 4-methylbenzene-1-sulfonyl chloride (1.4 g, 7.12 mmol) was added to the reaction mixture, which was stirred at room temperature for a further 24 hr. Water (40 mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (30-70% EtOAc/isohexane) gave 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl 4-methylbenzenesulfonate as a dark cream solid (2.81 g). This solid (2.3 g, 5.29 mmol) was treated with a solution of TBAF (1.0 M in THF, 21 mL, 21.1 mmol) and the reaction mixture was heated at 60° C. for 2 hr. After cooling to room temperature, water (30 mL) was added and the mixture was extracted with EtOAc (2×150 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (30-40% EtOAc/isohexane) gave 4-azido-5-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane as a yellow viscous oil (804 mg, 20% over two steps) 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 5.06 (ddt, J=46.2, 8.1, 2.5 Hz, 1H), 4.00 (dd, J=20.8, 8.1 Hz, 1H), 3.79 (s, 3H), 3.43-3.34 (m, 2H), 3.26-3.11 (m, 2H), 2.43-2.30 (m, 1H), 2.30-2.18 (m, 1H), 2.12-1.92 (m, 2H).
Reaction SMILES: [NH:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=2[N:4]=1)[NH2:2].[C:13]([CH:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17](OCC)=[O:18])(=O)[CH3:14].C(#N)C.O>C(O)(=O)C>[CH3:14][C:13]1[C:16]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:17]([OH:18])[N:1]([C:3]2[NH:7][C:6]3[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=3[N:4]=2)[N:2]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Reactant: Cc1ccc2[nH]c(NN)nc2c1
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: Cc1ccc2[nH]c(-n3nc(C)c(Cc4ccccc4)c3O)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-hydrazino-5-methyl-1H-benzimidazole (4) (1.0 g) and ethyl 2-acetyl-3-phenylpropanoate (1.4 mL) in acetic acid (20 mL) was stirred at room temperature for 2 hr. The reaction mixture was added to a mixture of acetonitrile (100 mL) and water (100 mL). After stirring at room temperature, the resulting precipitate was collected by filtration, and washed with a mixture of acetonitrile and water (1:1). The precipitate was recrystallized from ethanol (95 mL) to give 3-methyl-1-(5-methyl-1H-benzimidazol-2-yl)-4-(phenylmethyl)-1H-pyrazol-5-ol (5) (0.64 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C([Li])CCC.CN(C)[CH:19]=[O:20].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[O:20])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Brc1cc(Br)c2c(c1)CCO2
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1cc(Br)cc2c1OCC2
Reaction time: 8 h
Yield: 27.1 %

Procedure:
A sample of 19 (6.0 g, 26.5 mmol) in freshly distilled dry THF was degassed at −78° C. and n-butyllithium (25 mL of 1.05 M, 26 mmol) was added dropwise by syringe. Then N,N-dimethylformamide (2.9 mL, 26 mmol) was added dropwise via syringe. The reaction mixture was allowed to come to room temperature overnight. Saturated ammonium chloride (10 mL) was added to and the mixture was stirred for 30 minutes. The solvent was removed and the residue was taken up in dichloromethane (50 mL), and washed with water (3×50 mL) then dried with anhydrous sodium sulfate. Solvent removal yielded yellow crystals (1.6 g) which were washed with ether and recrystallized from a minimum of hot methanol to give white crystals of 20 (1.32 g, 22%) mp=99-100° C.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH3:22])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:23])[CH:5]=1.[CH3:24][C:25]1([CH3:32])[O:29][CH:28](CO)[CH2:27][O:26]1.O.[C:34]1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:24][C:25]1([CH3:32])[O:29][CH:28]([O:19][C:18](=[O:20])[CH:17]([CH3:34])[O:16][C:13]2[CH:12]=[C:11]3[C:3]([C:4]4[C:9]([CH2:21][CH3:22])([CH2:10]3)[CH2:8][CH2:7][C:6](=[O:23])[CH:5]=4)=[C:2]([Cl:1])[C:14]=2[Cl:15])[CH2:27][O:26]1
Reactant: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1(C)OCC(CO)O1
Solvent: O
Product: CCC12CCC(=O)C=C1c1c(cc(OC(C)C(=O)OC3COC(C)(C)O3)c(Cl)c1Cl)C2
Reaction time: 8 h

Procedure:
A mixture of 2 gm. of [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid, 3 ml. of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane and 0.5 g. of p-toluenesulfonic acid hydrate are heated on the steam bath for 3 hours. The dark reaction mixture then is chromatographed on 300 g of silica, and eluted with acetic acid-acetone-toluene (5:5:90). Fractions containing a single component (Rf~0.4) are pooled and concentrated to a yellow oil. On standing overnight, a mixture of crystalline solid and yellow oil resulted. The mixture is filtered and the solid recrystallized from tetrahydrofuran-ether-petroleum ether (5:15:25). The yield of pure product is 0.3 g., m.p. 143°-145° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].CI.CN(C=O)C.[CH3:14][C:15]1[N:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][C@@:24]2([C:37]3[CH:42]=[CH:41][C:40](O)=[C:39]([F:44])[CH:38]=3)[CH2:26][C@H:25]2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=2)=[O:28])=[CH:17][N:16]=1>O>[CH3:14][C:15]1[N:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][C@@:24]2([C:37]3[CH:42]=[CH:41][C:40]([O:4][CH3:1])=[C:39]([F:44])[CH:38]=3)[CH2:26][C@H:25]2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=2)=[O:28])=[CH:17][N:16]=1
Reactant: Cc1ncc(OC[C@@]2(c3ccc(O)c(F)c3)C[C@H]2C(=O)Nc2ccc(F)cn2)c(C)n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc([C@]2(COc3cnc(C)nc3C)C[C@H]2C(=O)Nc2ccc(F)cn2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
Cesium carbonate (172 mg) and methyl iodide (26.8 ul) were added to a DMF (5 ml) solution of the compound 321 (150 mg), and the obtained mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1 to 2:3), so as to obtain the title compound (70 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([C:11]1[N:16]=[C:15]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[N:14]=[C:13]([Cl:27])[CH:12]=1)[CH3:10]>CN(C)C=O>[ClH:27].[CH2:9]([C:11]1[N:16]=[C:15]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[N:14]=[C:13]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH:12]=1)[CH3:10]
Reactant: Nc1ccc(F)cc1
Reactant: CCc1cc(Cl)nc(N2CCc3ccccc3C2)n1
Solvent: CN(C)C=O
Product: CCc1cc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2)n1
Product: Cl
Yield: 78.3 %

Procedure:
After 4-fluoroaniline(0.30 ml, 3.17 mmol) was added to a mixture solution of 6-ethyl-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloropyrimidine(0.40 g, 1.46 mmol) and dimethylformamide(10 ml), 0.44 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.ClCC(=O)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:15]2=[CH:14][NH:13][N:12]=[C:11]2[NH:10][C:24]2[CH2:23][O:22][C:20](=[O:21])[C:19]1=2
Reactant: CCOC(=O)CC(=O)CCl
Reactant: O=Cc1ccccc1Cl
Reactant: Nc1cc[nH]n1
Product: O=C1OCC2=C1C(c1ccccc1Cl)c1c[nH]nc1N2

Procedure:
The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 4-chloroacetoacetate in the same manner as in Example 1.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[CH3:38][O:39][C:40](=[O:46])[C@@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1>CN(C=O)C.ClCCl>[CH3:38][O:39][C:40](=[O:46])[C@@H:41]1[CH2:45][CH2:44][CH2:43][N:42]1[C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C

Procedure:
To a solution of N-Cbz-valine (2.5 g, 10 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.6 g, 11 mmol) and triethylamine (2.0 g, 20 mmol) in DMF (10 mL) is added dropwise a solution of proline methyl ester hydrochloride (1.8 g, 11 mmol) in DMF (5 mL). The solution is stirred at room temperature and the reaction monitored by TLC until the disappearance of N-Cbz-valine. The reaction solution is then diluted with dichloromethane (30 mL) and the organic layer is extracted with 0.1 N HCl (20 mL), water (20 mL), then dried over Na2SO4. The solvent is removed in vacuo to afford the desired compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O[CH:12]=[C:13]([C:19]#[N:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C1(C)C=CC=CC=1>[C:19]([C:13](=[CH:12][NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:20]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: Cc1cccnc1N
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CNc1ncccc1C

Procedure:
A solution of 2-amino-3-methylpyridine (5.0 g., 0.0462 mole) and ethyl ethoxymethylenecyanoacetate (7.82 g., 0.0462 mole) in toluene (4 ml.) was heated for 15 minutes by means of an oil bath maintained at 100°. The solution was cooled and the title compound (9.1 g., 85%) collected by filtration. The product, m.p. 139°-143°, was recrystallized from 2-propanol to give an analytical sample, m.p. 144°-146°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)c(OC)c32)cc1OC
Reactant: NCc1ccccc1
Product: COc1ccc(CC2c3c(cc(OC)c(OC)c3OC)CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1.C([N:25](CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl.O>[N:13]1([NH:25][C:2]([Cl:1])=[O:4])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)CCCN2
Reactant: CCN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(Cl)NN1CCCc2ccccc21
Reaction time: 3 h

Procedure:
4.9 g of triphosgene are added to a solution of 5.5 g of 1,2,3,4-tetrahydroquinoline and 6.4 ml of triethylamine in 213 ml of dichloromethane at 0° C. The reaction mixture is stirred for 3 h and is then poured onto a mixture of water and ice. A saturated aqueous sodium hydrogencarbonate solution and dichloromethane are added. The aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with water and with a saturated aqueous sodium chloride solution and dried over sodium sulfate and then the solvent is evaporated under reduced pressure to result in 7.8 g of 3,4-dihydroquinoline-1(2H)-carbonyl chloride.