Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[Li]CCCC.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].[NH4+].[Cl-]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7]
Reactant: COc1cccc(CO)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: c1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)c1c(CO)cccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
2.00 g (14.5 mmol) of 3-methoxybenzyl alcohol were dissolved in 40 ml of dry benzene. At 0° C., 19.91 ml (31.9 mmol, 2.2 eq.) of a 1.6 molar n-BuLi solution were slowly added dropwise, where the white suspension formed after addition of one equivalent of n-BuLi changed its color to dark red during the addition of the second equivalent. Stirring at RT was continued for another 2 hours, and 5.1 ml (18.8 mmol, 1.3 eq.) of tributyltin chloride were then added at 0° C. The mixture was stirred at RT overnight, and 40 ml of saturated NH4Cl solution were then added and the mixture was extracted three times with 70 ml of EA. After washing of the organic phase with saturated NaCl solution and drying over MgSO4, the solvent was removed. The crude product was purified by column chromatography (reversed-phase silica RP-18, MeCN), which gave 4.83 g (11.3 mmol, 78%) of 3-methoxy-2-(tributylstannyl)benzyl alcohol as a colorless oil. In a further experiment, a yield of 60% was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:23])([CH3:22])[N:10](CC3C=CC(OC)=CC=3)[C:11](=[O:12])[C:6]2=[CH:5][CH:4]=1.O.CCOC(C)=O>CC#N>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:23])([CH3:22])[NH:10][C:11](=[O:12])[C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2C(=O)c3ccc(OC)nc3C2(C)C)cc1
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc2c(n1)C(C)(C)NC2=O
Yield: 62.4 %

Procedure:
To solution of 2-methoxy-6-(4-methoxy-benzyl)-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one (0.31 g, 1.0 mmol) in CH3CN (5 mL) was added ceric ammonium nitrate (1.64 g, 3.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours before water and EtOAc were added into the mixture. The organic layer was separated, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by silica gel column chromatography to give the title compound (0.12 g, 63%) as a solid. MS: 193.1 (M+H+).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]=4[C:16]=3[CH3:25])(=[O:14])=[O:13])[CH:9]=2)[CH2:4][CH2:3]1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH4-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]4[S:19][C:18]5[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]=5[C:16]=4[CH3:25])(=[O:14])=[O:13])[CH:9]=3)[CH2:4][CH2:3]2)[CH2:29][CH2:28]1
Reactant: Cc1c(S(=O)(=O)Nc2ccc3c(c2)C(=O)CC3)sc2ccc(Cl)cc12
Reactant: CN1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc3c(c2)C(N2CCN(C)CC2)CC3)sc2ccc(Cl)cc12
Temperature: 50 °C

Procedure:
A mixture of N-(3-oxo-2,3-dihydro-1H-inden-5-yl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide (100 mg, 0.26 mmol), 1-methylpiperazine (0.28 ml, 2.6 mmol) and titanium (IV) isopropoxide (0.1 ml, 0.33 mmol) was heated at 50° C. for 30 min. The material was dissolved in ethanol and sodium borohydride (11 mg, 0.29 mmol) was added. After stirring at reflux for 3 hours, 2N sodium carbonate was added. The mixture was filtered and the filtrate was concentrated in vacuo. The resulting crude was purified by chromatography on silica gel, using as an eluent mixtures of methylene chloride/methanol/ammonia yielding 80 mg (65%) of N-[3-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:19]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCNc1ccc(Cl)cc1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: CCOC(=O)CCN(C(=O)Cc1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.115.1, starting from 4-chlorophenylacetyl chloride and ethyl N-(4-chlorophenyl)-3-aminopropionate, ethyl 3-[2-(4-chloro-phenyl)-N-(4-chlorophenyl)acetamido]-propanoate was obtained as yellowish oil.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[NH2:25][CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: NCC(O)C(F)(F)F
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Product: O=C(NCC(O)C(F)(F)F)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 15 %

Procedure:
As described for example 325, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.61 mmol) was converted, using 3-amino-1,1,1,-trifluoropropan-2-ol instead of rac-2-amino-1-propanol, to the title compound (39 mg, 15%) which was obtained as a white solid MS: m/e=426.1 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CNC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of tert-butyl 2-hydroxypropylcarbamate (14.3 g, 81.7 mmol) and Et3N (35.6 ml, 245.1 mmol) in CH2Cl2 (250 mL) at 0° C. was slowly added a solution of methanesulfonyl chloride (9.5 mL, 122.6 mmol) in CH2Cl2 (250 mL). The mixture was stirred at 0° C. for 2 h, diluted with CH2Cl2 (300 mL) and washed with water, 1 N HCl, 5% NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to afford 1-(tert-butoxycarbonylamino)propan-2-yl methanesulfonate (19.5 g, 94%) as a light yellow oil. Mass calculated for C9H19NO5S=253.32. found: [M+H]+=254.2.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([O:25]C)=O)[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](=[O:25])[NH:35][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:17]=[CH:16]4)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC(=O)NCc2ccccc2)c1

Procedure:
Example 125 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 117) and benzylamine to give the title compound (0.002 g),
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][C:22]#[N:23]>>[CH3:16][O:17][C:18]1[CH:19]=[C:20](/[C:21](=[CH:12]/[C:11]2[CH:14]=[CH:15][C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:9][CH:10]=2)/[C:22]#[N:23])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COCCOCOc1ccc(C=O)cc1
Reactant: COc1ccc(CC#N)cc1OC
Product: COCCOCOc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Yield: 78.9 %

Procedure:
The hydroxyl group of 4-hydroxybenzaldehyde (24.9 g) was protected by use of 2-methoxyethoxymethyl chloride (24.4 g) in accordance with (production process 1), to thereby produce 4-methoxyethoxymethoxybenzaldehyde (33.5 g, yield: 80%). The thus-produced 4-methoxyethoxymethoxybenzaldehyde (21.0 g) and 3,4-dimethoxybenzyl cyanide (17.7 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce (Z)-2-(3,4-dimethoxyphenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]acrylonitrile (29.1 g, yield: 86%). Separately, 2-methoxyethoxymethyl chloride (4.1 g), which had been prepared in a manner similar to that described above, and 3,4-dimethoxybenzyl cyanide (3.4 g) were subjected to condensation in accordance with process B of (production process 2), to thereby produce (Z)-2-(3,4-dimethoxy-phenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]acrylonitrile (5.2 g, yield: 73%). The thus-produced (Z)-2-(3,4-dimethoxy-phenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]-acrylonitrile (10.2 g) was subjected to deprotection in accordance with (production process 3), to thereby produce the target product (6.22 g, yield: 74%).
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:20])[CH2:6][C:7](=[CH2:19])[CH:8](O)[CH:9]([NH:15][CH:16]=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].S(Br)([Br:23])=O.O>C(Cl)Cl>[C:1]([O:4][CH:5]([CH3:20])[CH2:6][C:7]([CH2:19][Br:23])=[CH:8][CH:9]([NH:15][CH:16]=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2]
Reactant: C=C(CC(C)OC(C)=O)C(O)C(NC=O)C(=O)OCC
Reactant: O=S(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C=C(CBr)CC(C)OC(C)=O)NC=O
Reaction time: 1 h

Procedure:
17.0 g (59.1 mmol) of ethyl 6-acetoxy-2-formylamino-3-hydroxy-4-methylene-heptanoate are dissolved in 170 ml of CH2Cl2 and 5.5 ml (71 mmol) of thionyl bromide are then added dropwise at room temperature. After 1 hour, 100 ml of water are added and the batch is vigorously stirred for 10 minutes. The organic phase is separated and washed once with water, once with a 1N solution of KHCO3 and twice with water. The aqueous phases are extracted twice with CH2Cl2. The combined organic phases are dried over MgSO4, filtered and concentrated by evaporation, giving ethyl 6-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoate as a brown oil which is further reacted without purification.
Reaction SMILES: [ClH:1].[C:2]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3]1>>[Cl:1][CH2:5][CH2:4][CH2:3][C:2]([OH:6])=[O:7].[C:2]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cl
Solvent: O=C1CCCO1
Product: O=C(O)CCCCl

Procedure:
Crude 4-chlorobutyric acid (CBA) was produced, in a known manner, by introducing gaseous hydrogen chloride into γ-butyrolactone (BL), at 100° C., until hydrogen chloride was no longer taken up. Subsequently, nitrogen was passed through the reaction mixture, in order to expel excess hydrogen chloride. The acid number was then 393. 1,818 g crude CBA was obtained from 1,373 g (15.8 mol) of BL.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1(/[CH:14]=[CH:15]/[C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22]C(C)(C)C)=[O:21])=[C:18]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH:17]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1(/[CH:14]=[CH:15]/[C:16]2[CH:28]=[CH:27][C:19]([C:20]([OH:22])=[O:21])=[C:18]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH:17]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/C2CCCCC2)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(/C=C/C2CCCCC2)cc1Nc1ccc(F)cc1

Procedure:
Trifluoroacetic acid 15 mL solution of the obtained tert-butyl 4-((E)-2-cyclohexylvinyl)-2-(4-fluoroanilino)benzoate was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give 4-((E)-2-cyclohexylvinyl)-2-(4-fluoroanilino)benzoic acid 34 mg of pale yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:17][CH2:16]2)[CH:10]([CH3:18])[CH2:9]1)=O)(C)(C)C.[O:19]1[C:23]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)=[CH:22][N:21]=[CH:20]1.O1C2(CCN(C#N)CC2)OCC1>>[CH:15]1([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[CH3:18])[C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([C:23]3[O:19][CH:20]=[N:21][CH:22]=3)=[CH:32][CH:31]=2)[CH2:16][CH2:17]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1NC1CC1
Reactant: O=C(O)c1ccc(-c2cnco2)cc1
Agent: N#CN1CCC2(CC1)OCCO2
Product: CC1CNCCC1N(C(=O)c1ccc(-c2cnco2)cc1)C1CC1

Procedure:
The title compound is prepared from 4-cyclopropylamino-3-methyl-piperidine-1-carboxylic acid tert-butyl ester and 4-oxazol-5-yl-benzoic acid following a procedure analogous to that described in Intermediate 1. LC (method 2): tR=0.84 min; Mass spectrum (ESI+): m/z=326 [M+H]+.
Reaction SMILES: [OH2:1].[OH-].[Li+].OO.[CH:6]1([CH2:11][C@H:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:13](N2[C@H](C)[C@H](C3C=CC=CC=3)OC2=O)=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7]1>C1COCC1>[CH:6]1([CH2:11][C@H:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:13]([OH:14])=[O:1])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](CC1CCCC1)c1ccccc1
Reactant: O
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Lithium hydroxide monohydrate (1.28 g, 30.6 mmol) is suspended in THF (50 mL) and cooled to 0° C. Hydrogen peroxide (50 wt % in water, 2.81 mL, 91.79 mmol) is added dropwise. Reaction is stirred at 0° C. for 15 min and the title C compound, (4R,5S)-3-((R)-3-cyclopentyl-2-phenyl-propionyl)-4-methyl-5-phenyl-oxazolidin-2-one (3.85 g, 10.2 mmol) is added in five separate portions, allowing portions to dissolve completely between additions. The reaction is allowed to stir and warm to RT overnight. The reaction is then concentrated to a sticky white solid. This is dissolved in ethyl acetate (25 mL)/1 N HCl (25 mL). The organic solution is dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product as a yellow oil. The crude product is chromatographed over silica eluting with 5→65% ethyl acetate in hexanes to afford (R)-3-cyclopentyl-2-phenyl -propionic acid as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.1 (m, J=11.6, 7.8, 7.8, 3.9 Hz, 2 H) 1.5 (m, 2 H) 1.6 (m, 2 H) 1.7; LC/MS 217.2 (M−1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]2[CH3:21])=[CH:4][CH:3]=1.Br[C:23]1[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[C:27]([Br:29])[CH:28]=1>>[Br:29][C:27]1[CH:28]=[C:23]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]3[CH3:21])=[CH:4][CH:3]=2)[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)nc1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Yield: 82.4 %

Procedure:
The procedures described in Example 104 and starting with 113b (4.0 g, 13.7 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (5.5 g, 20.6 mmol) afforded 113c as a yellow solid (5.4 g, 83%). See FIG. 13. MS-ESI: [M+H]+ 478
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:3]=12.C(N(CC)CC)C.[CH2:30]([C:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]>C(Cl)Cl>[CH2:30]([C:33]1([S:36]([N:11]2[C:4]3=[CH:5][C:6]4[S:10][CH:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: O=c1[nH]c2cc3scnc3c(F)c2n1-c1ccc(I)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(I)cc3F)c3c(F)c4ncsc4cc32)CC1

Procedure:
To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (50 mg, 0.12 mmol) in DCM (5 mL) was added triethylamine (35 mg, 0.74 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (32 mg, 0.18 mmol) and
Reaction SMILES: [F:1][C:2]([P:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])(=O)[OH:9])([F:7])[C:3]([F:6])([F:5])[F:4].C1(P(Cl)(Cl)(Cl)[Cl:25])C=CC=CC=1>>[F:1][C:2]([P:8]([Cl:25])([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[O:9])([F:7])[C:3]([F:6])([F:5])[F:4]
Reactant: ClP(Cl)(Cl)(Cl)c1ccccc1
Reactant: O=P(O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Product: O=P(Cl)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reaction time: 4 h
Yield: 78.4 %

Procedure:
21.75 g (72 mmol) of bis(pentafluoroethyl)phosphinic acid are added dropwise at room temperature to 20.0 g (80 mmol) of phenyltetrachlorophosphorane, and the mixture is stirred for four hours. Bis(pentafluoroethyl)phosphinyl chloride is separated off by distillation at atmospheric pressure, giving 18.1 g of bis(pentafluoroethyl)phosphinyl chloride, which corresponds to a yield of 78%, based on the phosphinic acid employed.
Reaction SMILES: [IH:1].[CH3:2][N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13](SC)=[NH:14])=[C:6]2[N:5]=[N:4]1.Cl.[NH2:18][CH2:19][C:20]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[O:21]>>[IH:1].[CH3:2][N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13](=[NH:14])[NH:18][CH2:19][C:20](=[O:21])[C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[C:6]2[N:5]=[N:4]1
Reactant: NCC(=O)c1cccs1
Reactant: CSC(=N)c1ncn2c(=O)n(C)nnc12
Agent: Cl
Agent: I
Product: Cn1nnc2c(C(=N)NCC(=O)c3cccs3)ncn2c1=O
Yield: 66 %

Procedure:
Using the general procedure, the title compound was synthesized from methyl 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbimidothioate hydroiodide and 2-amino-1-(thiophen-2-yl)ethanone hydrochloride, using a reaction time of 16 hours for the amidine formation. Yield 66%. δH (DMSO-d6): 9.76-9.73 (1H, m), 9.69 (1H, s), 9.49 (1H, bs), 9.22 (1H, s), 8.16 (1H, dd, J=4.9, 1.1), 8.12 (1H, dd, J=3.8, 1.1), 7.37 (1H, dd, J=4.9, 3.8), 5.17 (2H, d, J=6.3), 4.06 (3H, s).
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([F:12])=[CH:5][C:6]([CH3:11])=[C:7]([NH:9]N)[CH:8]=1.[O:13]1[CH:17]=[CH:16][CH2:15][CH2:14]1.Cl>C1COCC1.CCOCC.[Cl-].[Cl-].[Zn+2]>[CH3:11][C:6]12[C:16]([CH2:15][CH2:14][OH:13])=[CH:17][N:9]=[C:7]1[CH:8]=[C:3]([Br:2])[C:4]([F:12])=[CH:5]2
Reactant: Cc1cc(F)c(Br)cc1NN
Reactant: C1=COCC1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC12C=C(F)C(Br)=CC1=NC=C2CCO
Temperature: 0 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
To a solution of 5-bromo-4-fluoro-2-methylphenylhydrazine hydrochloride (4.75 g, 18.6 mmol) in 20% aqueous THF (100 mL) at 0° C. was added dropwise a solution of 2,3-dihydrofuran (1.55 mL, 20.4 mmol) in THF (10 mL). After stirring for 2 hours at 0° C. and 12 hours at room temperature, the reaction mixture was diluted with ether (100 mL). The organic solution was washed with saturated NaHCO3 (2×100 mL) and brine (100 mL), dried (Na2SO4) and concentrated. The residue was dissolved in ethylene glycol (50 mL), treated with ZnCl2 (5.58 g, 40.9 mmol), and heated at 170° C. for 4 hours. The reaction mixture was cooled down to room temperature and 6 N HCl (100 mL) was added. The mixture was extracted with ether (3×100 mL) and washed with water (200 mL) and brine (200 mL). The organic solution was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, 40% EtOAc in hexanes) to give 1.52 g (30%) of title compound containing inseparable impurities (<20%) as a light brown oil. 1H NMR (CDCl3): 300 MHz δ 8.68 (bs, 1H), 7.06 (d, J=2.4 Hz, 1H), 6.76 (d, J=9.63 Hz, 1H), 3.92 (t, J=6.48 Hz, 2H), 3.21 (t, J=6.48 Hz, 2H), 2.35 (s, 3H), 2.27 (bs, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([NH2:17])[C:5]=2[N:4]=1.[CH3:18][O:19][CH2:20][CH2:21][C@H:22]1[CH2:27]N[CH2:25][CH2:24][NH:23]1>>[CH3:18][O:19][CH2:20][CH2:21][C@@H:22]1[NH:23][CH2:24][CH2:25][N:17]([C:6]2[C:5]3[N:4]=[C:3]([CH3:2])[S:12][C:11]=3[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=2)[CH2:27]1
Reactant: COCC[C@H]1CNCCN1
Reactant: Cc1nc2c(s1)Nc1ccccc1N=C2N
Agent: Cl
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)nc32)CCN1

Procedure:
In a manner such as that described in Example 300, combine 2-methyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-ylamine hydrochloride (0.437 g, 1.64 mmol) and (S)-2-(2-methoxyethyl)piperazine (0.474 g, 3.29 mmol) to obtain the title compound: mass spectrum (APCI): m/z=358.0 (M+1).
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3].[Na].[F:12][C:13]([F:17])([F:16])[C:14]#[N:15]>COCCOC>[NH2:15]/[C:14](/[C:13]([F:17])([F:16])[F:12])=[C:5](/[C:1](=[O:4])[CH2:2][CH3:3])\[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(=O)CC
Reactant: N#CC(F)(F)F
Agent: [Na]
Solvent: COCCOC
Product: CCOC(=O)/C(C(=O)CC)=C(\N)C(F)(F)F

Procedure:
To a mechanically stirred solution of 287 g (1.99 mol) of ethyl propionylacetate in 500 ml of dry DME was added under nitrogen 8.6 g (0.348 mol) of freshly cut sodium. After all sodium had dissolved, 256 g (2.69 mol) of trifluoroacetonitrile was added over a 35 hour period. The reaction mixture was concentrated. The residue was washed with water and extracted into 500 ml of ether. The ether solution was dried and concentrated. The residue was kugelrohr distilled at 67 Pa. and then was redistilled at 67 Pa through a spinning band column. The first fraction (bp 40°-78° C.) was discarded. The next fraction (bp 79°-82° C.) was 151 g (31.6%) of product, nD25 1.4574.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CC=CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC=CCCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1, 2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.