Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].N1C=CN=C1.[CH3:11][C@H:12]([CH2:28][CH3:29])[C@:13]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)([OH:20])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1.O>CN(C)C=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]([O:20][Si:2]([CH3:4])([CH3:3])[CH3:1])([C@H:12]([CH3:11])[CH:28]=[CH2:29])[CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)=[CH:22][CH:23]=1
Reactant: CC[C@@H](C)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C=C[C@@H](C)[C@@](Cn1cncn1)(O[Si](C)(C)C)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 114.7 %

Procedure:
2.47 ml (19.4 mmole) of trimethylsilyl chloride and 1.7 g (24.3 mmole) of imidazole were added to a solution of 900 mg (3.24 mmole) of (2R*,3R*)-3-methyl-2-(4-chlorophenyl) -(1H-1,2,4-triazol-1-yl)-2-pentanol in 20 ml of N,N-dimethylformamide, and then the mixture was stirred at 50° C. for 4 hours. At the end of this time, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure to give 1.3 g of the title compound in the form of a crude oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[CH:17]([NH:21][C:22]1[CH:23]=[N:24][C:25]([N:28]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[N:29]2)=[CH:26][CH:27]=1)[CH2:18][CH2:19][CH3:20])[C:5]([NH:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=[O:6].[OH-].[Li+].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[CH:17]([NH:21][C:22]1[CH:23]=[N:24][C:25]([N:28]2[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[N:29]2)=[CH:26][CH:27]=1)[CH2:18][CH2:19][CH3:20])[C:5]([NH:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:6]
Reactant: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)nc1)c1ccc(C(=O)NCCC(=O)OC)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a solution of Isomer 1 of methyl 3-(3-fluoro-4-(1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamido)propanoate (180 mg, 0.36 mmol) in tetrahydrofuran (8 mL) was added 2 N aqueous lithium hydroxide (8 mL, 16 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was acidified to pH˜2 with 1 N aqueous hydrochloric acid and extracted with ethyl acetate (3×5 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to give 3-(3-fluoro-4-(1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamido)propanoic acid, Isomer 1 (104 mg, 59%) as a white solid. 1H NMR (400 MHz, CD3OD, δ): 8.57 (s, 1H), 7.77 (s, 1H), 7.63 (s, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.43-7.46 (m, 2H), 7.34-7.38 (m, 1H), 6.93 (d, J=8.8 Hz, 1H), 4.66 (t, J=6.8 Hz, 1H), 3.48 (t, J=6.8 Hz, 2H), 2.50 (t, J=6.8 Hz, 2H), 1.65-1.82 (m, 2H), 1.17-1.49 (m, 2H), 0.89 (t, J=6.8 Hz, 3H). MS (M+1) 494.2. Chiral SFC: Chiralpak AD-3, 4.6×50 mm, 3 μm. Modifier: 0.05% DEA. Gradient: 95% CO2/5% ethanol linear to 60% CO2/40% ethanol over 3.0 minutes. Flow: 4 mL/min. Retention time: 1.74 minutes, 100% ee (Isomer 1).
Reaction SMILES: [OH:1][CH:2]1[CH:6]=[CH:5][S:4][CH:3]1[C:7]#[N:8].[CH:9](Cl)(Cl)Cl>[N+](=C)=[N-].CCOCC>[CH3:9][O:1][CH:2]1[CH:6]=[CH:5][S:4][CH:3]1[C:7]#[N:8]
Reactant: N#CC1SC=CC1O
Reactant: ClC(Cl)Cl
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: COC1C=CSC1C#N
Temperature: 0 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
12.7 parts of 3-hydroxy-2-cyanodihydrothiophene are dissolved in 100 parts by volume of chloroform and 200 parts by volume of a 4 percent strength by weight solution of diazomethane in ether are added at 0° C. The solution is stirred for 12 hours at 0° C. and is concentrated under reduced pressure. The residue is distilled. 10.1 parts (72% of theory) of 3-methoxy-2-cyanodihydrothiophene of boiling point 82°-83° C./0.35 mbar are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:10][C:11]#[N:12])=[CH:5][CH:4]=1>O1CCOCC1.[Pd]>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][C:11]#[N:12])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=CC#N)c2ccc(OC)cc2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1ccc(C(CC#N)c2ccc(OC)cc2)cc1
Yield: 75.4 %

Procedure:
10% Pd—C (20 mg) was added to a solution of 3,3-bis (4-methoxyphenyl)-propenenitrile (50 mg), synthesized by the process described in a literature J. Med. Chem., 32, 1820 (1989), in dioxane (5 ml), followed by hydrogenation for 2 hr. Pd—C was removed by filtration through Celite. The solvent was then removed by distillation to give 3,3-bis(4-methoxyphenyl)-propanenitrile (38 mg).
Reaction SMILES: O.[S-2:2].[Na+].[Na+].[CH3:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Cl)=[CH:8][CH:7]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][S:2][CH2:5][C:6]2[CH:13]=[CH:12][C:9]([CH3:10])=[CH:8][CH:7]=2)=[CH:8][CH:7]=1
Reactant: [S-2]
Reactant: Cc1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(CSCc2ccc(C)cc2)cc1
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
A solution of 269.0 g (1.12 mol) of sodium sulfide hydrate and 12.0 g of tetrabutylammonium hydrogen sulfate (phase transfer catalyst) in 300 ml of water is introduced into a reaction vessel provided with a stirrer and thermometer. 212.6 g (1.52 mol) of 4-methylbenzyl chloride are added dropwise at below 40° C. in the course of 30 minutes (min), while stirring intensively. The reaction mixture is stirred at room temperature (RT) for 4 1/2 hours (h) and then at 50°-60° C. for 1/2 h. The reaction mixture is cooled to 0°-5° C. and kept at this temperature for 1/2 h. The reaction mixture is filtered and the residue is dissolved in about 2 liters of ethyl acetate. The organic phase is extracted twice by shaking with deionized water (pH ~6) and dried over MgSO4. The ethyl acetate is removed on a rotary evaporator. The residue is dried overnight at RT under a high vacuum. 174.8 g (95% of theory) of di-(p-methylbenzyl) sulfide are obtained as slightly yellowish white crystals having a melting point of 74°-76° C.
Reaction SMILES: [Br:1][C:2]1[S:6](=[O:8])(=[O:7])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[C:3]=1Br.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Br:1][C:2]1[S:6](=[O:8])(=[O:7])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[C:3]=1[O:23][C:20]1[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][CH:19]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1ccc2c(c1)S(=O)(=O)C(Br)=C2Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)S(=O)(=O)C(Br)=C2Oc1ccc(Br)cc1
Reaction time: 0.02 h
Yield: 98.4 %

Procedure:
To a solution of 2,3-dibromo-6-methoxybenzo[b]thiophene 1,1-dioxide (2.50 g, 7.06 mmol) in THF (100 mL) at room temperature was added 4-bromophenol (1.344 g, 7.77 mmol) and Cs2CO3 (6.90 g, 21.19 mmol). The reaction mixture turned green after ˜1 min of stirring. The mixture was stirred at room temperature for 18 h after which time the reaction was quenched with water and diluted with DCM. The organic layer was collected (phase separator) and concentrated to provide 2-bromo-3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (3.10 g, 6.95 mmol, 98% yield) as a white solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ ppm=3.83 (s, 3 H), 6.92-7.03 (m, 3 H), 7.25-7.35 (m, 2 H), 7.39-7.50 (m, 2 H).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2.[BH4-].[Na+].Cl.[CH3:25]O>>[CH3:25][O:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2
Reactant: CO
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)Cc1ccc2c(c1)C(OC)c1ccccc1CO2

Procedure:
A mixture of 5.64 g. of methyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate, 0.4 g. of sodium borohydride and 250 ml. of methanol is stirred at 0°-2° for four hours. The reaction product is treated with 1N hydrochloric acid and extracted with chloroform, and the chloroform extracts are washed with saturated sodium bicarbonate solution and dried with sodium sulfate. The chloroform is evaporated to leave methyl 6,11-dihydro-11-methoxydibenz[b,e]oxepin-2-acetate as an oil;
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cu](C#N)[C:13]#[N:14].Cl>CN1CCCC1=O.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:13]#[N:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: N#C[Cu]C#N
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc(N)c(C(=O)O)c1
Temperature: 190 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A solution of 2-amino-5-bromobenzoic acid (6.9 g, 31.9 mmol) in N-methyl-2-pyrrolidinone (100 mL) was treated with copper cyanide (4.14 g, 46 mmol) and the mixture was heated at 190° C. for 4.5 hours before being cooled to room temperature and allowed to stand overnight. The mixture was diluted with water (500 mL), acidified with 6N aqueous HCl (100 mL) and extracted with ethyl acetate (6×40 mL). The organic extracts were dried (MgSO4) and concentrated under reduced pressure to yield the crude nitrile (4.35 g, 84%).
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[N:32]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:29][CH:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C>CCOC(C)=O>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[N:32]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:29][CH:28]=3)=[CH:25][N:26]=2)=[O:8])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cccc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)n1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)n1
Yield: 35.1 %

Procedure:
The title compound was prepared from methyl 6-(2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)picolinate (70 mg, 0.138 mmol) following General Procedure C. Flash chromatography (10-30% EtOAc) yielded the title compound as a white solid (19 mg, 35%): 1H NMR (CDCl3, 500 MHz) δ 8.19 (d, 1H, J=7.0 Hz), 8.12-8.09 (m, 2H), 8.06-8.03 (m, 1H), 7.36-7.33 (m, 2H), 7.26-7.24 (m, 3H), 4.11 (s, 3H), 3.19 (t, 2H, J=7.0 Hz), 2.69 (t, 2H, J=7.5 Hz), 1.89-1.83 (m, 2H), 1.75-1.69 (m, 2H), 1.55-1.47 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 188.9, 165.5, 158.0, 152.7, 149.0, 147.0, 143.1, 138.7, 128.8, 128.7, 128.4, 126.0, 125.6, 123.7, 53.5, 39.6, 36.3, 31.7, 29.4, 29.4, 24.3; MALDI-FTMS m/z 393.1796 (M+H+, C23H25N2O4, requires 393.1809).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH3:11][NH:12][NH2:13]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:10])[N:12]([CH3:11])[NH2:13])=[CH:4][CH:3]=1
Reactant: CNN
Reactant: Fc1ccc(N=C=S)cc1
Solvent: CCO
Product: CN(N)C(=S)Nc1ccc(F)cc1
Yield: 76.9 %

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 10.0 g (0.0653 mole) of 4-fluorophenyl isothiocyanate with 3.01 g (0.0654 mole) of methylhydrazine in 100 ml of ethanol yielded 10 g of 4-(4-fluorophenyl)-2-methyl-3-thiosemicarbazide as a solid, mp 148°-150° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[C:29]([F:30])=[C:28](Cl)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:32][O:33][C@H:34]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@H:35]1[NH2:43].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[N:25]=[CH:26][N:27]=[C:28]([NH:43][C@@H:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:42][C@@H:34]3[O:33][CH3:32])[C:29]=2[F:30])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc(Cl)c2F)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CO[C@H]1Cc2ccccc2[C@H]1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1ncnc(O[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C2)c1F
Temperature: 180 °C
Yield: 95.6 %

Procedure:
4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-6-chloro-5-fluoropyrimidine (260 mg, 0.53 mmol), (1R,2S)-2-methoxyindan-1-amine (364 mg, 2.12 mmol), and sodium carbonate (224 mg, 2.12 mmol) was weighed into a microwave reaction tube. This mixture was heated in a sealed tube under microwave irradiation at 180° C. for 2 h. The reaction mixture was diluted with DCM (100 mL), and the suspension was filtered. The filtrate was washed with saturated NH4Cl solution (100 mL), and the organic layer was dried over MgSO4. This suspension was filtered, and evaporated under vacuum. The residue was purified via silica gel column chromatography eluting with a gradient of 0 to 10% methanol in DCM to afford the title compound (313 mg, 91%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH2:10]>>[C:9]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:8]
Reactant: Oc1ccccc1
Reactant: C=C(C)CC(C)(C)C
Product: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Reaction time: 20 h
Yield: 0.9 %

Procedure:
A suspension of 1,000 parts of phenol, 700 parts of diisobutylene and 40 parts of ion exchange resin is prepared in a stirred reactor at 100° C. and 1 bar pressure, the mixture being stirred at 500 rpm. The ion exchange resin is a sulfonated styrene/divinylbenzene copolymer resin, which has been dehydrated under reduced pressure for 20 hours at 100° C. before being used; it has a gel structure and its particle size is from 20 to 150 micrometers. The suspension is then stirred constantly in the reactor at 500 rpm. After 30 minutes, 1,000 parts of phenol and 700 parts of diisobutylene are introduced per hour at 100° C. and 1 bar pressure and correspondingly 1,700 parts per hour of suspension are filtered through a suction line equipped with a metal filter (pore diameter 10 micrometers) and are subjected to fractional distillation. After 100 hours' operation, 116,100 parts (86% of theory, based on starting material II) of 4-tert.-octylphenol of boiling point 160°-162° C./27 millibars are obtained, in addition to 3,400 parts (2.5% of theory, based on starting material II) of 2-tert.-octylphenol and 1,750 parts (0.9% of theory, based on starting material II) of tert.-butylphenol. The conversion is 54%, based on phenol employed, or 91%, based on starting material II.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]1[S:15][CH2:14][CH:13](OC(OC)=O)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:21]([O:30]C(C)C)([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24].C([O-])(O)=O.[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([O:9][CH2:10][CH:11]1[S:15][CH2:14][CH:13]([P:21]([O:26][CH:27]([CH3:29])[CH3:28])([O:22][CH:23]([CH3:25])[CH3:24])=[O:30])[O:12]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)OC1CSC(COC(=O)c2ccccc2)O1
Reactant: CC(C)OP(OC(C)C)OC(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)OP(=O)(OC(C)C)C1CSC(COC(=O)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-benzoyloxymethyl-5-(methyloxycarbonyloxy)-1,3-oxathiolane (4.80 g, 16.11 mmol) and triisopropyl phosphite (4.77 ml, 19.33 mmol) in dry dichloromethane (100 ml) at 0° C. was added dropwise titanium tetrachloride (1.77 ml, 16.11 mmol). After 2 h at 0° C., the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was then poured into saturated NaHCO3 (100 ml). The mixture was then filtered and the filtrate was partitioned. The aqueous layer was further extracted with dichloromethane (2×) and the combined extracts were washed with brine (1×), dried and concentrated. Chromatography eluting with 25-50% EtAc in hexanes yielded the title compound as a 1:1 cis trans mixture (4.958 g, 79%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([CH2:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])=[C:4]([CH3:15])[C:3]=1[C:16]([O:18]CC)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]#[N:31])[CH:25]=[CH:26][C:27]=1[Cl:28]>Cl.O1CCOCC1>[Cl:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:29][C:30]1[NH:31][C:16](=[O:18])[C:3]2[C:4]([CH3:15])=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])[S:6][C:2]=2[N:1]=1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: CCCCOC(=O)Cc1sc(N)c(C(=O)OCC)c1C
Agent: Cl
Solvent: C1COCCO1
Product: CCCCOC(=O)Cc1sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
A mixture of 900 mg of butyl 5-amino-4-ethoxycarbonyl-3-methyl-2-thiopheneacetate, 558 mg of (3,4-dichlorophenyl)acetonitrile and 20 mL of 4N hydrochloric acid/1,4-dioxane solution was stirred at room temperature overnight. Ice water was added to the reaction mixture, followed by neutralization with 25% aqueous ammonia, extraction with chloroform, drying over anhydrous magnesium sulfate and removal of the solvent by distillation under reduced pressure. The residue was purified on silica gel column chromatography (chloroform:methanol=50:1) to provide 500 mg (38%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=O)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36].[CH3:38][NH:39][CH3:40].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][N:39]([CH3:40])[CH3:38])=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36]
Reactant: CNC
Reactant: CCN(c1cc(-c2ccc(C=O)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(-c2ccc(CN(C)C)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.1 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(6-formylpyridin-3-yl)-2-methylbenzamide (0.102 g, 0.203 mmol) and dimethylamine (0.044 g, 2M 0.507 mL, 1.01 mmol) in dichloroethane (3 mL), acetic acid (0.073 g, 1.021 mmol) was added and reaction stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (0.129 g, 0.609 mmol) was added at 0° C. and reaction stirred for 4 h at room temperature. On completion, solvent was removed under reduced pressure and water was added, extraction was carried out using 10% MeOH/DCM. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure giving crude material which was purified by column chromatography to afford the title compound (0.08 g, 75%). LCMS: 532.30 (M+1)+; HPLC: 97.53% (@ 254 nm) (Rt; 3.878; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.75 (d, 1H, J=1.2 Hz), 8.20 (t, 1H, J=4.8 Hz), 8.02 (d, 1H, J=6.4 Hz), 7.49 (s, 1H), 7.47 (s, 1H), 7.27 (s, 1H), 5.87 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.81-3.84 (m, 2H), 3.56 (s, 2H), 3.22-3.24 (m, 2H), 3.02-3.12 (m, 3H), 2.25 (s, 3H), 2.21 (s, 6H), 2.20 (s, 3H), 2.10 (s, 3H), 1.65-1.67 (m, 2H), 1.50-1.56 (m, 2H), 0.82 (t, 3H, J=6.8 Hz).
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>>[NH2:17][C:16]1[C:4]([C:2]#[N:3])=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:23]([NH:22][CH2:20][CH3:21])=[O:24]
Reactant: CCN=C=O
Reactant: N#Cc1c(OC[C@@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Product: CCNC(=O)N1CCC[C@H]1COc1cccc(N)c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 191a from (S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 191b) and ethyl isocyanate in 100% yield as a white solid. MS 289 (MH+).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[NH:26][N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:38]([CH3:45])([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C)C=O>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[N:26]([C:38]([CH3:45])([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=c1[nH]nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)n1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.606 g of 6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was suspended in 3 ml of N,N-dimethylformamide; 0.063 g of 60% oily sodium hydride was added,-followed by stirring at room temperature for 1 hour. 0.253 ml of ethyl 2-bromoisobutyrate was added, followed by stirring in an oil bath (bath temperature 80° C.) for 17 hours. After cooling, 0.063 g of 60% oily sodium hydride and 0.253 ml of ethyl 2-bromoisobutyrate were added, followed by stirring in an oil bath (bath temperature 80° C.) for 3 hours. After cooling, ice water was added; the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (90:10:1). The desired fraction was collected and concentrated to yield 0.38 g of ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate as an oily substance. This oily substance was dissolved in 5 ml of ethyl acetate; 0.5 ml of a 4 N solution of hydrogen chloride in ethyl acetate was added, followed by concentration; the residue was powdered from diethyl ether, collected by filtration, and dried, to yield 0.342 g of the title compound.