Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C@H:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2].Cl.O.[N:46]1([CH2:52][CH:53]=O)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C([BH3-])#N>CO>[CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C@H:23]2[CH2:27][CH2:26][N:25]([CH2:53][CH2:52][N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)[CH2:24]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2]
Reactant: O=CCN1CCOCC1
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C[C@H]2CCNC2)cn1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C[C@H]2CCN(CCN3CCOCC3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A vial was charged with (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate (Example 234, 800 mg, 1.3 mmol) and morpholin-4-yl-acetaldehyde monohydrate hydrochloride (270 mg, 1.47 mmol) in methanol (10 mL). MP-cyanoborohydride (850 mg, 2.0 mmol) beads were added and the resulting mixture was allowed to stir at room temperature overnight. The mixture was filtered and the beads were washed with more methanol. The filtrate was concentrated and purified by Analogix SF15-24 g in DCM/methanol system to give a light yellow solid (380 mg, 45.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH2:15][NH2:16]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([NH2:13])[NH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=O)CC#N)cc1F
Reactant: NN
Solvent: CCO
Product: COc1ccc(-c2cc(N)[nH]n2)cc1F

Procedure:
3-(3-Fluoro-4-methoxyphenyl)-3-oxopropanenitrile (2.13 g, 11 mmol) and hydrazine (0.38 mL, 12.13 mmol) were combined in absolute ethanol and the reaction mixture was heated to reflux overnight. Then, the solvent and excess hydrazine were evaporated to provide the title compound in quantitative yield.
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([CH2:9][F:10])[CH:8]=1.[OH-].[Na+].[F:14][C:15]([F:22])([F:21])[C:16]([F:20])=[C:17]([F:19])[F:18]>CC(C)=O.O>[F:18][C:17]([O:11][C:5]1[CH:4]=[C:3]([CH2:2][F:1])[CH:8]=[C:7]([CH2:9][F:10])[CH:6]=1)([F:19])[CH:16]([F:20])[C:15]([F:22])([F:21])[F:14]
Reactant: Oc1cc(CF)cc(CF)c1
Reactant: FC(F)=C(F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: FCc1cc(CF)cc(OC(F)(F)C(F)C(F)(F)F)c1

Procedure:
490 g of 3,5-bis-fluoromethyl-phenol were placed in 1000 ml of acetone together with 50 g of 50% by weight aqueous sodium hydroxide solution, and hexafluoropropene was introduced at 25° C. up to the saturation point. The batch was then diluted with 11 of water and the organic phase was separated off, dried and distilled to give 673 g of 3,5-bis-fluoromethyl-phenyl 1,1,2,3,3,3-hexafluoropropyl ether with a boiling point of 65° to 70° C. at 22 mbar and a refractive index nD2 of 1.3560.
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:29]\[OH:30])/[C@:18]5([OH:28])[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(CCC(=[O:51])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[OH:28][C@:18]12[CH2:19][C:20](=[O:51])[CH2:21][CH2:22][C@:23]1([CH3:24])[C@@H:25]1[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]1)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]3)[CH2:16]/[C:17]/2=[N:29]\[OH:30]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CC[C@H]3[C@@H](C/C(=N\O)[C@@]4(O)CCCC[C@]34C)[C@@H]1CC13OCCOC12OCCO3
Product: C[C@]12CC[C@H]3[C@@H](C/C(=N\O)[C@@]4(O)CC(=O)CC[C@]34C)[C@@H]1CCC2=O
Yield: 80 %

Procedure:
The title compound II-bm was prepared in 80% yield from 3,3:17,17-bis(ethylendioxy)-5α-hydroxy-6-(E)-hydroxyiminoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/acetone/CH2Cl2 60/20/20). 1H-NMR (300 MHz, acetone-d6, ppm from TMS: δ 10.72 (s, 1H), 5.35 (s, 1H), 3.12 (dd, 1H), 2.85-1.09 (m, 18H), 0.94 (s, 3H), 0.78 (s, 3H).
Reaction SMILES: Cl[Si:2]1([CH:7]([Cl:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1>>[Cl:9][CH:7]([Si:2]1([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1)[CH3:8]
Reactant: CC(Cl)[Si]1(Cl)CCCC1
Reactant: Fc1ccc([Mg]Br)cc1
Product: CC(Cl)[Si]1(c2ccc(F)cc2)CCCC1

Procedure:
In the same apparatus and procedures as Example 1 was reacted 40 ml of 4-fluorophenylmagnesiumbromide solution (2.0 M in diethylether) with 1-chloro-1-(α-chloroehtyl)-1-silacyclopentane prepared from the above procedure i) for 5hrs. In the same method as Example 1 was treated the reaction product to give 4.8 g of 1-(α-chloroethyl)-1-(4-fluorophenyl)-silacyclopentane (84°-5° C./0.3 mmHg).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([C:15]1[C:20]([Cl:21])=[C:19]([CH3:22])[CH:18]=[C:17]([N+:23]([O-:25])=[O:24])[C:16]=1[OH:26])[CH:13]=[CH2:14]>C(Cl)Cl>[Cl:21][C:20]1[C:15]2[CH2:12][CH:13]([CH2:14][OH:9])[O:26][C:16]=2[C:17]([N+:23]([O-:25])=[O:24])=[CH:18][C:19]=1[CH3:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1c(O)c([N+](=O)[O-])cc(C)c1Cl
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c2c(c1Cl)CC(CO)O2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
53 g of 85% MCPBA was added to a solution of 54 g of 7B in 500 ml of methylene chloride, and the mixture was stirred for 20 hours in the dark at room temperature, then filtered. The filtrate was washed with sodium bicarbonate solution, dried (MgSO4) and the solvent was evaporated. The residue was chromatographed over silica gel, using a 1:4:20 v:v:v mixture of tetrahydrofuran, ethyl acetate and hexane as eluent. The solid product that was obtained was recrystallized from ether to give 4-chloro-2,3-dihydro-2-(hydroxymethyl)-5-methyl-7-nitrobenzofuran (7C), as a light yellow solid, m.p.: 112°-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[NH:10][CH2:11][C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[CH:5][C:4]=1B(O)O.Cl[C:23]1[N:28]=[N:27][C:26]([N:29]([CH3:40])[CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[O:18])=[CH:5][C:4]=1[C:23]1[N:28]=[N:27][C:26]([N:29]([CH3:40])[CH:30]2[CH2:35][C:34]([CH3:36])([CH3:37])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C(=O)NCc2cnn(C)c2)cc1B(O)O
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Product: COc1ccc(C(=O)NCc2cnn(C)c2)cc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Yield: 100.2 %

Procedure:
Following standard GENERAL METHOD 1-4 for Suzuki coupling using (2-methoxy-5-(((1-methyl-1H-pyrazol-4-yl)methyl)carbamoyl)phenyl)boronic acid (613 mg, 2.12 mmol) and 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 1-1, 300 mg, 1.06 mmol) afforded 4-methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)benzamide (522 mg) MS [M+H+]=492.6.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:13]=[C:12]2[N:14]=[CH:15][NH:16][C:11]2=[C:10]([Cl:17])[CH:9]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:21]=1[CH3:30]>CN(C)C=O>[Cl:7][C:8]1[N:13]=[C:12]2[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[C:21]=3[CH3:30])[CH:15]=[N:16][C:11]2=[C:10]([Cl:17])[CH:9]=1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: Clc1cc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cn2cnc3c(Cl)cc(Cl)nc32)cccc1C(F)(F)F
Reaction time: 0.42 h
Yield: 47.6 %

Procedure:
Potassium carbonate (1139 mg, 8.24 mmol) was added to a solution of 5,7-dichloro-1H-imidazo[4,5-b]pyridine (500 mg, 2.66 mmol) in N,N-Dimethylformamide (DMF) (8.5 mL) and the mixture was stirred for 25 min. 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (942 mg, 3.72 mmol) was then added and the reaction mixture was stirred at rt overnight. The mixture was partitioned between water and EtOAc. The aqueous layer was extracted with additional EtOAc (2×25 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified on silica gel (15 to 30% EtOAc in hexanes) to give 5,7-dichloro-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (456 mg, 1.266 mmol, 47.6% yield) as an off-white powder. MS (ES+) m/e 359 (MH+) 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (s, 1H), 7.68 (s, 1H), 7.66 (d, J=8.08 Hz, 1H), 7.33 (t, J=7.71 Hz, 1H), 7.07 (d, J=7.83 Hz, 1H), 5.62 (s, 2H) (Ar—CH3 hidden under DMSO peak).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1[C:4]#[N:5].Cl.[NH+]1C=CC=CC=1.O>C(OC)(C)(C)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:5]
Reactant: COc1cccc(F)c1C#N
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: COC(C)(C)C
Solvent: O
Product: N#Cc1c(O)cccc1F
Temperature: 190 °C
Reaction time: 5 h

Procedure:
151 g (1 mol) of 2-fluoro-6-methoxybenzonitrile and 346.5 g (3 mol) of pyridinium hydrochloride were introduced into a 2 l flask and then slowly heated to 190° C. under a protective gas atmosphere and then stirred at this temperature for 5 h. The mixture was cooled by slowly stirring to room temperature overnight. Then 1000 ml of water were added, and the mixture was heated to 80° C. After adding 1000 ml of methyl tert.-butyl ether, the phases were separated and the aqueous phase was back-extracted twice with 500 ml of methyl tert.-butyl ether. The combined methyl tert.-butyl ether phases were washed once with 800 ml of 10% strength aqueous sodium hydroxide solution and once with 400 ml of water. The two aqueous phases were combined, adjusted to pH 2 with concentrated hydrochloric acid and washed three times with 500 ml of methylene chloride. Then, the combined organic phases were washed once with 10% strength hydrochloric acid. The organic phase was dried over sodium sulfate. Finally, the solvent was distilled off in vacuo. Yield: 120 g (87% of theory) of the desired product of purity >99% according to GC. 1H NMR (in D6 dimethylsulfoxide): δ=6.85 ppm (m, 2H, arom. H), 7.55 ppm (q, 1H, arom. H), 11.7 ppm (s, 1H, OH).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:19]=[C:18]([NH:20]/[C:21](/[NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:22]\[C:23](=[O:34])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[NH:17][N:16]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:36]([NH:35]/[C:21](/[NH:20][C:18]1[NH:17][N:16]=[C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])[CH:19]=1)=[N:22]/[C:23](=[O:34])[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)N/C(=N/C(=O)c1ccc(C(F)(F)F)cc1)Nc1cc(-c2ccccc2OCc2ccccc2)n[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)N/C(=N/C(=O)c1ccc(C(F)(F)F)cc1)Nc1cc(-c2ccccc2O)n[nH]1
Yield: 43.7 %

Procedure:
(Z)—N-(((3-(2-(Benzyloxy)phenyl)-1H-pyrazol-5-yl)amino)(tert-butylamino)methylene)-4-(trifluoromethyl)benzamide (190 mg) was dissolved in methanol (10 mL) and the solution was degassed with nitrogen. To the solution was added 10% palladium on carbon (38 mg, 0.1 equiv). The resulting mixture was subjected to hydrogen gas at 30 psi pressure in a Parr shaker. The reaction was checked periodically for completion. Upon reaction completion, the mixture was filtered through celite, and the filtrate was concentrated in vacuo to provide the crude product, which was purified by silica chromatography (9:1 to 55:45 hexanes:EtOAc) to provide the title compound (69 mg, 44% yield). 1HNMR (400 MHz, DMSO-d6) δ 12.79 (bm, 2H), 10.32 (bs, 1H), 9.05 (s, 1H), 8.28 (d, 2H), 7.82 (d, 2H), 7.61 (d, 1H), 7.19 (t, 1H), 6.95 (d, 1H), 6.86 (t, 1H), 6.53 (s, 1H), 4.06 (m, 1H), 3.14 (s, 1H), 1.56 (s, 9H); MS (EI+) m/z: 446.00, 467.97; HPLC (Method B): 6.15 min
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=12)=[O:4].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH2:23][C:24]1[N:29]=[C:28](Cl)[CH:27]=[C:26]([Cl:31])[N:25]=1.CCOC(C)=O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[CH:13]=[C:12]([O:14][C:28]3[CH:27]=[C:26]([Cl:31])[N:25]=[C:24]([NH2:23])[N:29]=3)[CH:11]=[CH:10][C:9]=12)=[O:4]
Reactant: COC(=O)c1cnn2cc(O)ccc12
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnn2cc(Oc3cc(Cl)nc(N)n3)ccc12
Temperature: 70 °C
Reaction time: 20 h

Procedure:
58.9 mg Product from Step 15.6 (0.31 mMol) are dissolved in 8 ml NMP and treated with 268 mg (1.2 mMol) K3PO4 and 75 mg (0.46 mMol) 2-amino-4,6-dichloropyrimidine at rt. The reaction mixture is warmed to 70° C. and stirred for 20 h at rt. It is worked up by addition of EtOAc and washed with H2O. The organic layer is dried and concentrated to give the crude product which is purified by recrystallization from EtOAc to give the title compound as a white powder: MS: [M+1]+=320; 1H MNR (DMSO-d6): δ ppm 9.18 (s, 1H), 8.43 (s, 1H), 8.09 (d, 1H), 7.60 (d, 1H), 7.21 (bs, 2H, NH2), 6.42 (s, 1H), 3.82 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]([NH:25][CH3:26])=[O:24])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][NH:19]3)=[O:15])[CH:9]=2)=[CH:6][N:7]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH2:1][C:2]1[C:3]([C:23]([NH:25][CH3:26])=[O:24])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][N:19]3[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:15])[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(C(=O)NCC3CCCN3)c2)cnc1N
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC(=O)c1nc(-c2cccc(C(=O)NCC3CCCN3Cc3ccccc3)c2)cnc1N
Reaction time: 1 h
Yield: 225 %

Procedure:
To a stirred solution of 3-amino-N-methyl-6-(3-{[(pyrrolidin-2-ylmethyl)amino]carbonyl}phenyl)pyrazine-2-carboxamide (35.4 mg, 0.01 mmol) and benzaldehyde (24.8 mg, 0.02 mmol) in methanol (3 mL) was added sodium cyanoborohydride (25 mg, 0.04 mmol). The mixture was stirred for 1 h and then acetic acid added until the pH of the solution was 7.0. The solution was stirred for an additional 6 h, solvent was removed and residue was partitioned with CHCl3 and 2 M aqueous sodium hydroxide (5 mL). The aqueous phase was extracted with additional CHCl3 (2×5 mL) and the combined organic layer were washed with saturated aqueous sodium chloride then dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography provided 10 mg of 3-amino-N-methyl-6-{3-[({[1-(phenylmethyl)pyrrolidin-2-yl]methyl}amino)carbonyl]phenyl}pyrazine-2-carboxamide: 1H NMR (400 MHz; CDCl3); 8.7 (s, 1H); 8.65 (s, 1H); 8.28 (br s, 1H); 7.95 (d, 1H); 7.22 (d, 1H); 7.53 (t, 1H); 7.2-7.4 (m, 5H); 4.3-3.5 (m, 7H); 2.95 (d, 3H); 2.35-1.8 (m, 4H); MS (EI) for C25H28N6O2: 445 )
Reaction SMILES: [N:1]1([CH2:6][C:7]23[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:15][C:9]([SH:17])([CH2:10]4)[CH2:8]2)[CH2:14]3)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:18][O-].[Na+].IC>CO>[CH3:18][S:17][C:9]12[CH2:10][CH:11]3[CH2:12][CH:13]([CH2:14][C:7]([CH2:6][N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)([CH2:16]3)[CH2:8]1)[CH2:15]2
Reactant: C[O-]
Reactant: SC12CC3CC(C1)CC(Cn1cccn1)(C3)C2
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSC12CC3CC(CC(Cn4cccn4)(C3)C1)C2
Temperature: 25 °C

Procedure:
To a solution of EXAMPLE 81A (300 mg) in methanol (2 mL) was added sodium methoxide (4 mL, 0.5 M in methanol). Iodomethane (0.5 mL) was added, and the reaction heated to reflux for 3 hours. The reaction was cooled to room temperature and concentrated to dryness. The residue war purified by reverse phase HPLC, eluting with a gradient of 30% to 100% acetonitrile in water containing 0.1% v/v trifluoroacetic acid, to give the title product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:11][S:10][C:9](=[S:12])[CH:8]=2)[CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20]Br)=[CH:17][CH:16]=1.[I-:25].[Na+]>CC(C)=O.C(Cl)Cl>[I-:25].[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20][S:12][C:9]2[S:10][S:11][C:7](=[N+:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:8]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: S=c1cc(N2CCOCC2)ss1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccc(C(=O)CSc2cc(=[N+]3CCOCC3)ss2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A suspension of 5-morpholino-1,2-dithiol-3-thione (2.62 g), 4-methoxyphenacyl bromide (4.12 g) and sodium iodide (3 g) in acetone (60 cc) is heated to the reflux temperature and maintained there for 2 hours. After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed successively with acetone (30 cc), distilled water (2×40 cc) and acetone (2×30 cc). The product thus obtained is suspended in methylene chloride (110 cc). After stirring for 1 hour at a temperature of about 20° C., the insoluble product is separated by filtration. N-[5-(4-Methoxyphenacylthio)-1,2-dithiol-3-ylidene]-morpholinium iodide, melting at 152°-155° C., is thus obtained.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][Cl:29])=[CH:23][CH:22]=2)[C:12]([NH2:19])=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16]>>[Cl:8][C:9]1[C:14]([C:15]([F:16])([F:17])[F:18])=[CH:13][C:12]2[N:19]=[C:3]([C:2]([OH:1])([CH3:7])[CH3:6])[N:20]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][Cl:29])=[CH:23][CH:22]=3)[C:11]=2[CH:10]=1
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1Nc1ccc(CCCl)cc1
Reactant: CC(C)(O)C(=O)O
Product: CC(C)(O)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCCl)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 339, step 3 & Example 1, step 5 from 2-hydroxyisobutyric acid and 4-chloro-N2-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1,2-benzenediamine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1(C)C=CC(S([CH2:21][N+:22]#[C-:23])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:9]=[C:8]([C:10]2[O:11][CH:23]=[N:22][CH:21]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: N#Cc1ccc(C=O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#Cc1ccc(-c2cnco2)cc1F
Yield: 434.7 %

Procedure:
To a 100 mL round-bottom flask was added 2-fluoro-4-formylbenzonitrile 37 (1.00 g, 6.7 mmol), methanol (25 mL), p-toluene sulfonylmethyl isocyanide (1.44 g, 7.37 mmol), followed by potassium carbonate (1.195 g, 8.64 mmol). The reaction mixture was stirred at reflux for about 1.5 hour and followed by TLC. The solvent was then evaporated and saturated aq.NaHCO3 was added. The resultant suspension was extracted with CH2Cl2 (2×20 mL). Combined organic layers were washed with brine, dried (anhydrous Na2SO4), and concentrated to leave a yellow solid. Crude product was further purified by MPLC (Biotage) silica column chromatography (Acetone/hexane as an eluent) to afford 2-fluoro-4-(oxazol-5-yl)benzonitrile 38 (5.48 g, 79% yield). MS (ES) m/z 189 (M+H+).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:18]2[CH2:23][CH2:22][CH2:21][NH:20][N:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH3:8].Cl.[CH3:25][C:26]1[N:27]=[C:28]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[S:29][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:31]([C:30]3[S:29][C:28]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[N:27][C:26]=3[CH3:25])=[O:32])[N:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH3:8]
Reactant: CCOc1cc(C2=NNCCC2)ccc1OC
Reactant: Cc1nc(-c2cccnc2)sc1C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1cc(C2=NN(C(=O)c3sc(-c4cccnc4)nc3C)CCC2)ccc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
1 ml of pyridine is added to a solution of 1.1 g of 3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine in 20 ml of DCM, and 1.2 g of 4-methyl-2-pyridin-3-ylthiazole-5-carbonyl chloride, hydrochloride (“BA”) are subsequently added, and the mixture is stirred at room temperature for a further 16 hours. Conventional work-up gives 1.7 g of 1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-pyridin-3-ylthiazol-5-yl)methanone.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][CH2:10][CH2:11][CH2:12][NH2:13].[CH2:14]([N:20]=[C:21]=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(Cl)Cl>[Cl:9][CH2:10][CH2:11][CH2:12][NH:13][C:21]([NH:20][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:22]
Reactant: CCCCCCN=C=O
Reactant: NCCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCNC(=O)NCCCCl
Reaction time: 1 h
Yield: 86.1 %

Procedure:
Triethylamine (35 g; 35 mmole) was slowly added to a mixture of chloropropylamine hydrochloride (39 g; 0.3 mol), n-hexyl isocyanate (38.2 g; 0.3 mole) and methylene chloride (500 ml). The resulting solution was stirred for one hour, and then the solvent was removed in vacuo. The residue was treated with ether, and the colorless solid was filtered off. The ether solution was then washed with water, dried (magnesium sulfate) and concentrated to give pure 1-(3-chloropropyl)-3-n-hexylurea (57.0 g; 86% yield) as colorless crystals, m.p. 48°-50° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([CH:10]([CH3:15])[C:11]([O:13]C)=[O:12])=[C:5]([F:16])[CH:4]=1.[O:17]=[C:18]1[CH2:22][CH2:21][CH2:20][CH:19]1C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:9][C:7]1[CH:8]=[C:3]([CH2:2][CH:19]2[CH2:20][CH2:21][CH2:22][C:18]2=[O:17])[CH:4]=[C:5]([F:16])[C:6]=1[CH:10]([CH3:15])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(C)c1c(F)cc(CBr)cc1F
Reactant: COC(=O)C1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C(=O)O)c1c(F)cc(CC2CCCC2=O)cc1F
Yield: 80.3 %

Procedure:
Compound (32b) (2.2 g, 7.5 mmol), methyl 2-oxocyclopentane-carboxylate (1.3 mL, 11.3 mmol), and anhydrous potassium carbonate (1.9 g, 13.6 mmol) in acetone (100 mL) were allowed to react in the same manner as in Example 15. The obtained crude product was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution followed by conventional decarboxylation and hydrolysis to give 1.7 g (64%) of compound (33b) of interest as clear yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:4].O>C(O)C>[CH3:15][O:14][C:10]1[CH:11]=[CH:12][C:13]2[CH2:2][C:3](=[O:4])[NH:5][CH2:6][CH2:7][C:8]=2[CH:9]=1
Reactant: COc1cccc(CCNC(=O)CCl)c1
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CCNC(=O)C2

Procedure:
A quantity of 3.1 gm (0.0136 mol) of N-chloroacetyl-N-(2-(3-methoxy-phenyl)-ethyl)-amine is dissolved in 270 ml of ethanol and 1530 ml of water and illuminated for ten hours under a nitrogen atmosphere with a mercury high pressure lamp at 20° to 25° C. The solution is concentrated down to about 400 ml, mixed with sodium bicarbonate, and extracted several times with ethyl acetate. The extracts are dried over magnesium sulfate and concentrated by evaporation, and the residue is purified over a silica gel column with ethyl acetate as eluant.