Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2([C:15]([OH:17])=[O:16])[CH:10]([CH2:11]2)[CH2:9]1)=O)(C)(C)C.[ClH:18].[CH3:19]O>O1CCOCC1>[ClH:18].[CH:10]12[CH2:11][C:12]1([C:15]([O:17][CH3:19])=[O:16])[CH2:13][CH2:14][NH:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)N1CCC2(C(=O)O)CC2C1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C12CCNCC1C2
Temperature: 60 °C
Yield: 101 %

Procedure:
3-[(tert-Butoxy)carbonyl]-3-azabicyclo[4.1.0]heptane-6-carboxylic acid (5 g, 20.72 mmol) was dissolved in MeOH (200 mL) and 4M HCl in 1,4-dioxane (25.9 mL) was added. The reaction mixture was heated at 60° C. for 4 h. The reaction mixture was cooled to room temperature, then concentrated, to afford the title compound (4.0 g, 101%) as a pale yellow solid. δH (250 MHz, CDCl3) 3.69 (s, 3H), 3.42 (br s, 1H), 2.11 (br s, 5H), 1.84 (br s, 1H), 1.62 (d, J 4.2 Hz, 1H), 1.29 (br s, 1H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][O-:19].[Na+].[Na]>CO>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:19][CH3:18])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C[O-]
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
1.5 g of 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile are added to a solution of sodium methylate in methanol prepared from 0.16 g of sodium and 20 ml of absolute methanol, and the mixture is heated to reflux temperature for 1 hour. The solvent is subsequently distilled off, the residue is treated with water and the resulting aqueous mixture is extracted three times with methylene chloride. The combined extracts are washed with water, dried over anhydrous sodium sulphate and evaporated. In this manner there is obtained methyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as an oil.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH3:25])[N:13]=[C:12]([NH2:26])[N:11]=2)[CH:7]=[CH:6][C:5]=1[Cl:27].[Li+].[OH-]>C1COCC1.O>[NH2:26][C:12]1[N:11]=[C:10]([C:8]2[CH:7]=[CH:6][C:5]([Cl:27])=[C:4]([CH:9]=2)[C:3]([OH:28])=[O:2])[C:15]([C:16]#[C:17][C:18]2[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[C:14]([CH3:25])[N:13]=1
Reactant: COC(=O)c1cc(-c2nc(N)nc(C)c2C#Cc2ccc(N)nc2)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(N)nc(-c2ccc(Cl)c(C(=O)O)c2)c1C#Cc1ccc(N)nc1
Yield: 59.5 %

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 2.28 g (5.78 mmol) 5-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-2-chloro-benzoic acid methyl ester using 347 mg (14.4 mmol.) LiOH in 20 mL THF and 1 mL water. The product precipitates and is isolated by filtration. The product is washed with water/acetonitrile (1:1 v/v) yielding 1.30 g (3.44 mmol) desired product, which is used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[CH3:15][S-:16].[Na+]>CS(C)=O.O>[CH3:15][S:16][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of N-(2-bromoethyl)phthalimide (500 mg) in DMSO (8 mL) was added sodium thiomethoxide (152 mg) and the reaction stirred at room temperature for 16 h. Then with water (2 mL) was added and the mixture stirred at room temperature for 10 min. The reaction was diluted with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4) and reduced in vacuo to give 2-(2-methylsulfanyl-ethyl)-isoindole-1,3-dione as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([N:27]([CH2:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:25][CH:26]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: Ic1ccc(N(Cc2ccncc2)c2ncccn2)cc1
Product: COC(=O)C(C/C=C/c1ccc(N(Cc2ccncc2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 73.9 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (72 mg) was reacted with N-(4-iodophenyl)-N-((pyridin-4-yl)methyl)pyrimidin-2-amine (93 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(pyridin-4-ylmethyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (99 mg). Column chromatography (silica gel, eluent: cyclohexane/ethyl acetate=1/2→1/3) was used for purification.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.C(OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:33]([C@@H:38]([C@H:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[OH:41])O)([O:35][CH2:36][CH3:37])=[O:34]>C1(C)C=CC=CC=1>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([CH:7]3[O:41][CH:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:38]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[O:8]3)=[CH:5][C:4]=2[O:9]1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(OCC)OCC
Product: CCOC(=O)C1OC(c2ccc3c(c2)OCO3)OC1C(=O)OCC
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of piperonal (60 g, 0.4 mol), triethyl orthoformate (59.2 g, 0.4 mol), toluene (250 mL) and p-toluenesulfonic acid (2 g, 0.01 mol) was heated at 100°-110° C. for 0.5 h. Diethyl L-tartrate (103 g, 0.5 mol) was added to the hot solution over a 10 min. period. The mixture was then heated at reflux for 2 h. Subsequently over a 3 hour period, distillate (150 mL) was collected (pot temperature 84° C. to 110° C). The mixture was cooled (25° C.) and washed with sodium bicarbonate solution (2×50 mL) and brine (1×50 mL). Evaporation of solvents under reduced pressure provided 130.7 g of crude product. Recrystallization from methanol provided 90 g (67% yield) of (4R,5R)-2-(3,4-methylenedioxyphenyl-4,5-dicarboethoxy-1,3-dioxolane, mp 39°-40° C., [α]D25 -34.8° (c, 1.0 methanol). 1H-NMR (CDCl3)δ7.12 (1H,d,J=1.5 Hz), 7.03 (1H,dd,J= 1.5 Hz and 7.9 Hz), 6.80 (1H,d,J=7.9 Hz), 6.06 (1H,s), 5.97 (2H,s), 4.91 (1H,d,J=4.0 Hz), 4.80 (1H,d,J=4.0 Hz), 4.36-4.26 (4H, 2 q, overlapping, J=7.0 Hz), 1.38-1.30 (6H, 2 t, overlapping, J=7.0 Hz). IR (KBr) 2980, 2900, 1735, 1490, 1445, 1415 cm-1. MS m/e (% abundance) 338 (3), 265 (16), 166 (100), 149 (96), 135 (54), 121 (35), 93 (10), 65 (12), 43 (8).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccccc1
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1ccccc1
Reaction time: 2 h

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)benzenesulfonamide (19 mg, 0.033 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[C:1]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C1CCNCC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCCCC1

Procedure:
The same procedures as in Example 1 were carried out using (E)-2-decenoic acid and piperidine as starting raw materials, to produce an intended compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:16])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:15])([O-])=O.O.O.[Sn](Cl)Cl.C(O)C.[OH-].[Na+]>O>[NH2:1][C:4]1[C:5]([CH3:16])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:15]
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c(C)ccnc12
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)c(C)c2c(C)ccnc12
Temperature: 25 °C

Procedure:
A mixture of 6-nitro-4,5,8-trimethylquinoline (0.60 g), tin(II)chloride dihydrate (3.13 g), and ethanol (40 mL) is heated for 3 hours at 60°-65° C. and then cooled to room temperature. 10% Aqueous sodium hydroxide (24 mL) and water (48 mL) are added, and the mixture is extracted three times with chloroform. The combined organic layers are washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated to afford a crude product. The crude product is purified by flash chromatography using 25% ethyl acetate in hexane as eluent, providing 6-amino-4,5,8-trimethylquinoline.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][N:16]=[C:17]([CH3:18])[C:11]=2[N:10]=[C:9]1[CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:27]Br.CCOC(C)=O>C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][N:16]=[C:17]([CH3:18])[C:11]=2[N:10]=[C:9]1[CH:19]([Br:27])[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1nc2c(C)nsc2c(=O)n1Cc1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCC(Br)c1nc2c(C)nsc2c(=O)n1Cc1ccccc1
Temperature: 0 °C

Procedure:
To a solution of 6-benzyl-3-methyl-5-propyl-6H-isothiazolo[4,5-d]pyrimidin-7-one (method 59) (208 mg, 0.69 mmol) and sodium acetate (0.5 g, 5 mmol) in acetic acid (10 mL) at 100° C., a solution of the bromine (0.232 g, 1.46 mmol) in acetic acid (20 mL) was added dropwise [The next drop of Bromine was added only after the previous drop had reacted completely by monitoring the decolorization] over a period of 30 min. The reaction mixture was cooled after the addition and the TLC (eluent 10% EtOAc in hexanes) and MS showed the complete disappearance of the SM and only the product. The reaction mixture was poured into ice water and extracted with EtOAc (3×30 mL) and the organic layers were combined and washed with 2% sodium thiosulfate solution (30 mL), water (50 mL), brine (50 mL) and dried (Na2SO4). Concentration of the organic layer provided the product and it was pure enough to be used in the next step. Yield 260 mg (99%). 1H NMR (300 MHz) δ 0.77 (t, 3H), 2.20-2.54 (m, 2H), 2.70 (s, 3H), 4.67 (t, 1H), 4.95 (d, 1H), 6.25 (d, 1H) 7.10-7.19 (m, 2H), 7.30-7.39 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[NH:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][C:13]([O:22][CH3:23])=[CH:14][C:15]=3[O:20][CH3:21])[N:10]=2)=[CH:4][C:3]=1[CH3:24].[CH:25]([N:28]([CH:31](C)C)[CH2:29]C)(C)C.CS(Cl)(=O)=O>CN(C=O)C.CCOC(C)=O>[CH3:21][O:20][C:15]1[CH:14]=[C:13]([O:22][CH3:23])[CH:12]=[C:11]2[C:16]=1[C:17](=[O:19])[NH:18][C:9]([C:5]1[CH:6]=[C:7]([CH3:8])[C:2](/[N:1]=[CH:25]/[N:28]([CH3:31])[CH3:29])=[C:3]([CH3:24])[CH:4]=1)=[N:10]2
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(N)c(C)c3)nc2c1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(/N=C/N(C)C)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.7 %

Procedure:
To a solution of 2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.096 g, 0.295 mmol) and diisopropylethylamine (61.7 μL, 0.354 mmol), in DMF (2.96 mL) was added dropwise methanesulfonyl chloride (25.2 μL, 0.325 mmol). After stirring at room temperature for 18 h, the mixture was diluted with EtOAc (300 mL), washed with saturated aqueous sodium bicarbonate (2×75 mL), saturated aqueous LiCl (2×75 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified over silica gel (12 g, CH2Cl2/CH3OH) to provide (E)-N′-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-N,N-dimethylformimidamide (0.0502 g, 45%) as a white solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.87 (s, 2H), 7.40 (s, 1H), 6.72 (d, J=2.31 Hz, 1H), 6.48 (d, J 2.31 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.97 (s, 6H), 2.12 (s, 6H); MS (APCI) m/z 381 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)[CH:10]([CH3:12])[CH3:11].[Br:26]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[Br:26][CH2:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)[CH:10]([CH3:12])[CH3:11]
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)N(CCCCOCCO)C1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: CC(C)N(CCCCOCCBr)C1CCN(Cc2ccccc2)CC1

Procedure:
4-[N-(7-Hydroxy-5-oxahept-1-yl)-N-(isopropyl)amino]-1-benzylpiperidine (2.0 g, 5.7 mmol) was treated with dibromotriphenylphosphorane (6.1 g, 14.4 mmol) in dichloromethane for 2 h. The reaction mixture was then was washed with 1 N sodium hydroxide, saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give the title intermediate, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C@:8]23[CH2:15][C@H:14]2[CH2:13][CH2:12][S:11][C:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:9]3)[CH:7]=1.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1)#[N:26]>>[C:25]([C:27]1[CH:28]=[CH:29][C:30]([C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C@:8]34[CH2:15][C@H:14]3[CH2:13][CH2:12][S:11][C:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:9]4)[CH:7]=2)=[O:34])=[N:31][CH:32]=1)#[N:26]
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)C[C@H]2CCS1
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(C#N)cn4)ccc3F)C[C@H]2CCS1
Yield: 46.5 %

Procedure:
Prepared in an analogous manner as described for intermediate rac-A9a from tert-butyl (1S,7S)-1-(5-amino-2-fluorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (intermediate (−)-A8a) (86.7 mg, 247 μmol) and commercially available 5-cyanopicolinic acid to give the tert-butyl (1S,7S)-1-(5-(5-cyanopicolinamido)-2-fluorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (65 mg, 135 μmol, 46.5% yield) as a yellow oil. MS (ISP): m/z=482.1 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:37]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38]1>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][C:25]([S:28][CH3:29])=[CH:26][CH:27]=4)[C@@H:19]([NH:21][S:40]([CH:37]4[CH2:39][CH2:38]4)(=[O:42])=[O:41])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CSc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NS(=O)(=O)C2CC2)cc1

Procedure:
(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(methylthio)phenyl]propan-2-amine (29a, 100 mg, 0.24 mmol) was dissolved in MeCN (3 mL), triethylamine (0.104 mL, 0.75 mmol) was added followed by addition of cyclopropane sulfonylchloride (0.025 mL, 0.25 mmol). The reaction was followed by LC/MS. After 1 hour approximately 50% conversion was detected, more reagents cyclopropane sulfonylchloride (0.025 mL, 0.25 mmol) and triethylamine (0.07 mL, 0.50 mmol) were added in an attempt to increase conversion without any success. The reaction was quenched by addition of saturated NH4Cl (aq) and concentrated. The residual material was purified by HPLC, collected fractions was freeze dried to give the title compound as a colourless solid. Chiral HPLC was made using an Chiralpak IB™, 150×0.46 mm column, 15% EtOH in iso-Hexane, 0.5 mL/min, UV=254 nm, one major peak at 32.39 min (99.7%) and one minor peak at 30.69 min (0.3%).
Reaction SMILES: [CH2:1]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:29](Br)[CH:30]=[CH2:31].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH2:31]([N:19]1[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:17]([CH:14]2[CH2:15][CH2:16][N:11]([C:9](=[O:10])[C:8]3[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:28][CH:27]=3)[CH2:12][CH2:13]2)[C:18]1=[O:26])[CH:30]=[CH2:29]
Reactant: CCCCc1ccc(C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)n(C2CCN(C(=O)c3ccc(CCCC)cc3)CC2)c2ccccc21
Temperature: 120 °C
Reaction time: 72 h
Yield: 66.1 %

Procedure:
1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (197.2 mg, 0.522 mmol), allyl bromide (260 μL, 3.0 mmol) and cesium carbonate (excess) were added to dimethyl formamide (3 mL) and the suspension was stirred at 120° C. in a sealed tube for 72 hours. The reaction was allowed to cool to room temperature and diluted with water (9 mL) then extracted with ethyl ether (2×10 mL). The combined organic phase was dried over sodium sulfate and purified by column chromatography on silica gel using ethyl ether as the eluent. The product fractions were combined and concentrated to give an oily residue. The residue was triturated with ethyl ether and the white crystals that formed were collected by filtration. Vacuum drying yielded 1-allyl-3-[1-(4-butyl-benzoyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (144 mg, 66%) as a white crystalline solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:29])[C:7](=[O:28])[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=1.[C:30]([O:34][C:35]([N:37]1[CH2:40][C:39](=[CH2:41])[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:30]([O:34][C:35]([N:37]1[CH2:40][C:39](=[CH:41][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[C:16]([F:18])([F:17])[F:19])[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:29])[C:7](=[O:28])[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[N:9]=2)[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(Br)cc3N21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(C=C4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 20.3 %

Procedure:
A solution of 6-bromo-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Example #53, Step E, 0.30 g, 0.61 mmol), 3-methylene-azetidine-1-carboxylic acid tert-butyl ester (0.123 g, 0.73 mmol), Pd(OAc)2 (0.027 g, 0.12 mmol), tri-O-tolylphosphine (0.074 g, 0.24 mmol) and triethylamine (0.184 g, 1.82 mmol) in CH3CN (10 mL) was heated at 110° C. for 14 hr. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by preparative TLC (eluting with 25% EtOAc in petroleum ether) to give 3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylmethylene]-azetidine-1-carboxylic acid tert-butyl ester (0.072 g, 20%) as a yellow solid. LC/MS (Table 1, Method 2) Rt=1.523 min.; MS m/z: 605 [M+23]+.
Reaction SMILES: [K].[F:2][C:3]1[C:4](=[S:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH2:11](I)[CH3:12]>CO>[CH2:11]([S:10][C:4]1[C:3]([F:2])=[CH:8][NH:7][C:6](=[O:9])[N:5]=1)[CH3:12]
Reactant: O=c1[nH]cc(F)c(=S)[nH]1
Reactant: CCI
Agent: [K]
Solvent: CO
Product: CCSc1nc(=O)[nH]cc1F
Yield: 70 %

Procedure:
The potassium salt of 5-fluoro-4-thiouracil (0.0065 mol) and ethyl iodide (0.014 mol) in methanol (40 ml) were stirred at room temperature for 6 days. The solutions were concentrated at reduced pressure and water (6 ml) added. The slowly precipitated product was recrystallised from water; yield 70%, m.p. 168° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3]C(C)(C)C)=O.[C:12]1([CH3:21])[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=C=O)[CH:13]=1>C(#N)C>[CH3:21][C:12]1[CH:13]=[C:14]([NH:18][C:1]([NH:8][CH2:9][CH2:10][NH2:11])=[O:3])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CC#N
Product: Cc1cccc(NC(=O)NCCN)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
N-Boc-Ethylene diamine (800 mg, 5 mmol) and m-tolyl isocyanate (665 mg, 5 mmol) were dissolved in acetonitrile and the mixture stirred at room temperature for 4 hrs. Solvent was removed under reduced pressure and the residue absorbed onto silica gel; prior to purification by flash column chromatography (silica, hexane:EtOAc 1:1) to yield the desired compound as a white solid (300 mg, 21%) (MS (+ESI, m/e) 294 (M+H)+). The N-Boc protected compound (300 mg, 1.02 mmol) was dissolved in formic acid (10 ml) and the mixture stirred at room temperature overnight. Excess acid was removed to yield the formate salt of the title compound as a white foam (210 mg).
Reaction SMILES: C([NH:8][C:9]1[C:18]([Cl:19])=[C:17]2[C:12]([C:13](=[O:41])[C:14]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:15][N:16]2[C:20]2[CH:25]=[C:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([F:34])=[CH:22][C:21]=2[F:35])=[CH:11][C:10]=1[F:42])C1C=CC=CC=1.C(O)(=O)C.[H][H]>ClCCCl.[OH-].[Pd+2].[OH-]>[NH2:8][C:9]1[C:18]([Cl:19])=[C:17]2[C:12]([C:13](=[O:41])[C:14]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:15][N:16]2[C:20]2[CH:25]=[C:24]([NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C:23]([F:34])=[CH:22][C:21]=2[F:35])=[CH:11][C:10]=1[F:42]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(NCc3ccccc3)c(F)cc2c1=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(N)c(F)cc2c1=O
Temperature: 25 °C
Yield: 91.9 %

Procedure:
Ethyl 7-benzylamino-1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (3.2 g) was dissolved in 1,2-dichloroethane (40 ml). An acetic acid suspension (10 ml) of 20% palladium hydroxide (300 mg) was added to this solution, and the mixture was stirred overnight at 60° C. in a hydrogen atmosphere. An acetic acid suspension (4 ml) of 20% palladium hydroxide (100 mg) was additionally added, and the resultant mixture was stirred overnight at the same temperature. After the reaction mixture was cooled back to room temperature, palladium hydroxide was removed by filtration. After the solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue, and solids were collected by filtration to obtain the title compound (2.5 g) as an amorphous substance.