Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:21][O:22][C:23](=[O:25])[N:24]=2)[CH:15]=1.[CH3:28][O:29][N:30]([CH3:34])[C:31](Cl)=[O:32]>N1C=CC=CC=1>[F:27][C:13]([F:12])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[N:24]([C:31]([N:30]([O:29][CH3:28])[CH3:34])=[O:32])[C:23](=[O:25])[O:22][N:21]=2)[CH:15]=1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: CON(C)C(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CON(C)C(=O)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
To 1 ml of pyridine were added 0.18 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.15 g of N-methoxy-N-methylcarbamoyl chloride was added at room temperature. After stirring at 50° C. for 4 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.19 g of 3-(4-trifluoromethylpyridin-2-yl)-N-methoxy-N-methyl-1,2,4-oxadiazol-5-one-4-carboxamide (present compound (21))
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:17])[CH2:12][C:13]([CH2:15]Br)=O)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[CH3:21][NH:22][C:23]([NH2:25])=[S:24].C(=O)(O)[O-].[Na+]>O>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([CH2:12][C:13]2[N:25]=[C:23]([NH:22][CH3:21])[S:24][CH:15]=2)=[O:17])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(N)=S
Reactant: CC(C)(C)c1nnc(NC(=O)CC(=O)CBr)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNc1nc(CC(=O)Nc2nnc(C(C)(C)C)s2)cs1
Yield: 87.2 %

Procedure:
A reaction mixture containing 11.4 g (0.035 mole) of N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-4-bromoacetoacetamide, 150 ml of ethanol and 3.3 g (0.036 mole) of N-methylthiourea was refluxed for 4 hours. The reaction solution was poured into 300 ml of water and treated with excess aqueous sodium bicarbonate. The product was isolated and dried. There was obtained 9.5 g (87.2%) of white solid, m.p. 198°-200° (dec.). N.M.R. (CDCl3) ∂ 1.4 [C(CH3)3 ], 3.0 (CH3), 3.8 (CH2), 6.4 (hetero-aromatic).
Reaction SMILES: O[C:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:6].C(NCC)C.C([OH:22])C>>[CH3:13][C:2]1([CH3:14])[C:3](=[O:22])[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[O:6]1
Reactant: CC(C)(O)C#CC(=O)c1ccncc1
Reactant: CCO
Solvent: CCNCC
Product: CC1(C)OC(c2ccncc2)=CC1=O
Reaction time: 1 h

Procedure:
To a stirred solution of 4-hydroxy-4-methyl-1-(pyridin-4-yl)pent-2-yn-1-one (1.8 g, 9.50 mmol) in ethanol (18 mL) was added diethyl amine (1.04 g, 14.0 mmol) in EtOH (1 mL) dropwise at RT and the reaction mixture was stirred for additional 1 h. The reaction mixture was concentrated, diluted with EtOAc (20 mL), washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford crude 2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (1.3 g) as an oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.Cl.[NH2:19][C@H:20]([C:23]([OH:25])=[O:24])[CH2:21][SH:22].C(O)C>O>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][S:22][CH2:21][C@@H:20]([C:23]([OH:25])=[O:24])[NH2:19])=[CH:12][CH:11]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(CSC[C@H](N)C(=O)O)cc1
Reaction time: 16 h
Yield: 78.3 %

Procedure:
Triethylamine (206 g) and 4-methoxybenzyl chloride (89 g) were added in turn to a solution of cysteine hydrochloride (107 g) in a 2:1 v/v mixture of ethanol and water (1000 ml). The mixture was stirred at laboratory temperature for 16 hours. The mixture was filtered to give S-(4-methoxybenzyl)cysteine (107.4 g). The filtrate was stored -10° C. for 48 hours and a second crop (22.3 g) of the cysteine derivative was obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]1[C:18]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=[O:25])[CH2:17][CH2:16][CH2:15][CH2:14]1.[C:26](=O)([O:29]C)[O:27][CH3:28].CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[O:25]=[C:19]1[CH:20]([C:26]([O:27][CH3:28])=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][C:18]21[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2
Reactant: COC(=O)OC
Reactant: O=C1CCCCCC12CCCCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: COC(=O)C1CCCCC2(CCCCC2)C1=O
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (1.130 mL, 7.93 mmol) in THF (10 mL) was treated with n-butyllithium (3.17 mL, 7.93 mmol) at −78° C., and the reaction was stirred at this temperature for 30 minutes. The above solution was then transferred via cannula into a solution of the product from Example 16A (1.1 g, 6.10 mmol) in THF (10 mL) at −78° C., and the resulting mixture was stirred at this temperature for 30 minutes. Dimethyl carbonate (5.14 mL, 61.0 mmol) was added, the cold bath was removed, and HMPA (1.062 mL, 6.10 mmol) was then added. The resulting mixture was stirred at ambient temperature for 16 hours. It was quenched with HCl (1N) and diluted with ether (200 mL), then the organic layer was separated, washed with H2O and brine, dried with MgSO4, and concentrated under reduced pressure. The residue was chromatographed on silica gel (95:5 hexane-EtOAc, eluant) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 3.88 (dd, J=11.87, 3.05 Hz, 1 H), 3.68 (s, 3 H), 2.06-2.16 (m, 1 H), 1.92-2.04 (m, 2 H), 1.59-1.90 (m, 5 H), 1.29-1.51 (m, 8 H), 0.98-1.16 (m, 2 H). MS (DCI+) m/z 239 (M+H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([C:19](=[O:22])[CH:20]=[CH2:21])[CH:18]=1)(C(C)(C)C)(C)C.C1COCC1>C(O)(=O)C>[OH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([C:19](=[O:22])[CH:20]=[CH2:21])[CH:18]=1
Reactant: C=CC(=O)c1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CC(=O)c1cc(OCCCO)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
1-(5'-[3"-(t-Butyidimethylsilyloxy)propyloxy]-2'-nitrophenyl]-2-propen-1-one (the compound of Example 31-(2)) (1.84 g) is mixed with THF (20 ml) and 50% aqueous acetic acid solution (30 ml), and the mixture is stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give 1-[5'-(3"-hydroxypropyloxy)-2'-nitrophenyl]-2-propen-1-one (1.26 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=1.C([O-])(=O)C.[Na+].[H][H]>CCOCC.[Pd]>[F:9][C:7]1[CH:8]=[C:3]([CH3:2])[CH:4]=[C:5]([F:10])[CH:6]=1
Reactant: [H][H]
Reactant: Fc1cc(F)cc(CBr)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cc(F)cc(F)c1
Yield: 98.1 %

Procedure:
A mixture of 1-bromomethyl-3,5-difluoro-benzene (75 g, 0.362 mol), Pd/C (5%, 5 g), and sodium acetate (208 g, 2.54 mol) in ether (300 mL) was treated with hydrogen gas (50 psi) in a Parr shaker for 2 days. The mixture was filtered through Celite and the organic solution washed three times with saturated aqueous sodium bicarbonate solution. The aqueous layers were washed with ether and the combined organic layers dried (MgSO4), filtered, and partially concentrated by evaporation using a cold water bath. The volatile product was obtained as a mixture with ether and the ratio (˜3:2, ether:product, g:g) calculated based on 1H NMR integration to determine actual yield (45.5 g, 0.355 mol, 98%) of product for scaling reagents in the ensuing reaction. 1H NMR (400 MHz, CDCl3) δ 2.25 (s, 3H), 6.51-6.56 (m, 1H), 6.58-6.60 (m, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[N:12]=[C:11]([C:21]([N:23]3[CH2:27][CH2:26][S:25][CH2:24]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C(N3CCS(=O)C3)=[O:48])C=2)C=C(F)C=1.ClC1C=CC=C(C(OO)=O)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[N:12]=[C:11]([C:21]([N:23]3[CH2:27][CH2:26][S:25](=[O:48])[CH2:24]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1cc(-n2nc(C(=O)N3CCSC3)cc2-c2cc(F)cc(Cl)c2)ccn1
Reactant: O=C(c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1)N1CCS(=O)C1
Agent: O=C(OO)c1cccc(Cl)c1
Product: Cc1cc(-n2nc(C(=O)N3CCS(=O)C3)cc2-c2cc(F)cc(Cl)c2)ccn1

Procedure:
55 mg (0.14 mmol) of the compound of Example 23 is reacted analogously to the synthesis of the compound of Example 6 with 34 mg (0.14 mmol, 70%) of meta-chloroperbenzoic acid for 2 hours at room temperature. After the crude product is purified by means of preparative HPLC (mobile solvent: acetonitrile/water gradient), 53 mg (93% of theory) of the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]([NH2:15])=[O:14])(=[O:11])=[O:10].[NH:16]1[CH2:20][CH2:19][CH:18]=N1>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]([N:15]1[CH2:18][CH2:19][CH:20]=[N:16]1)=[O:14])(=[O:11])=[O:10]
Reactant: NC(=O)NS(=O)(=O)c1c(F)cccc1F
Reactant: C1=NNCC1
Solvent: C1COCCO1
Product: O=C(NS(=O)(=O)c1c(F)cccc1F)N1CCC=N1

Procedure:
N-(2,6-difluorophenylsulphonyl)urea in an amount of 2.36 and 1.40 g of 2-pyrazoline in 20 ml of dioxane are refluxed for 4 hours. After evaporation of the solvent at reduced pressure, the remaining solid is dissolved in 20 ml of water. This solution is filtrated and acidified with conc. hydrochloric acid. The precipitate is sucked off, washed with water and dried, yielding the title product, viz. 1-(2,6-difluorophenylsulphonylcarbamoyl)-2-pyrazoline in a yield of 1.87 g; melting point 183° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:7]=3[NH:8]2)=[CH:4][C:3]=1[O:16][CH3:17].C([OH:20])C.[OH-].[K+]>O>[NH2:12][CH2:13][CH2:14][C:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[C:3]([O:16][CH3:17])[CH:4]=2)[NH:8][C:7]=1[C:11]([OH:20])=[O:15]
Reactant: COc1cc2c3c([nH]c2cc1F)C(=O)NCC3
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(CCN)c(C(=O)O)[nH]c2cc1F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a mixture of 7-fluoro-6-methoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (780 mg), ethanol (5.00 mL), and water (5.00 mL) was added potassium hydroxide (1.58 g), followed by stirring at 80° C. overnight. Potassium hydroxide (1.58 g) was added to the reaction mixture, followed by stirring at 100° C. for 6 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in water (10.0 mL), to the mixture was added acetic acid (3.00 mL), and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 3-(2-aminoethyl)-6-fluoro-5-methoxy-1H-indole-2-carboxylic acid (607 mg) as a reddish brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([C:8](=O)[CH:9]([F:11])[F:10])[CH:7]=1.[CH3:14][C:15]([S@@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6](/[C:8](=[N:20]\[S@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])/[CH:9]([F:11])[F:10])[CH:7]=1
Reactant: O=C(c1cc(Br)ccc1F)C(F)F
Reactant: CC(C)(C)[S@@](N)=O
Product: CC(C)(C)[S@](=O)/N=C(\c1cc(Br)ccc1F)C(F)F
Yield: 78 %

Procedure:
Starting from 1-(5-bromo-2-fluorophenyl)-2,2-difluoroethanone and (S)-(−)-2-methyl-2-propanesulfinamide, the (S,E)-N-(1-(5-bromo-2-fluorophenyl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide (14.49 g, 78.0% yield) was obtained as a yellow oil. MS (ISP): m/z=355.9 [M+H]+ and 357.9 [M+2+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:20]=[CH:19][C:18]3[N:17]([CH3:21])[C:16]4[CH2:22][CH:23]5[NH:27][CH:26]([C:15]=4[C:14]=3[C:13]=2C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>>[ClH:1].[Cl:8][C:6]1[CH:5]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]2[CH2:22][CH:23]4[NH:27][CH:26]([C:15]3=2)[CH2:25][CH2:24]4)(=[O:11])=[O:10])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cc(Cl)cc(Cl)c4)ccc31)C1CCC(C2)N1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Cn1c2c(c3cc(S(=O)(=O)c4cc(Cl)cc(Cl)c4)ccc31)C1CCC(C2)N1

Procedure:
The product of step A was Boc-deprotected with TFA following the procedure of Example 28, Step B. The crude material was purified by flash column chromatography (SiO2, 90:9:1 dichloromethane/methanol/ammonium hydroxide) followed by semi-preparative HPLC. The free base was treated directly with 1.25 M HCl in methanol (2 mL) and the solution concentrated in vacuo to give 2-(3,5-dichlorophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (15 mg, 31%, AUC HPLC 98.9%) as an off-white solid: mp 190-195° C.; 1H NMR (CD3OD, 300 MHz) δ 8.32 (s, 1H), 7.88 (d, J=1.8 Hz, 2H), 7.58-7.78 (m, 3H), 5.28-5.38 (m, 1H), 4.55 (br s, 1H), 3.72 (s, 3H), 3.40-3.60 (m, 1H), 3.02-3.17 (m, 1H), 2.22-2.55 (m, 3H), 1.92-2.07 (m, 1H); ESI MS m/z 421 [M+H]+.
Reaction SMILES: C([O:8][C:9](=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([CH3:22])[N:19]=[N:18]2)=[C:13]([F:23])[CH:12]=1)C1C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:35][C:36]([CH3:38])=[O:37].C(OCC)(=[O:41])C>>[F:23][C:13]1[CH:12]=[C:11]([N:10]2[CH2:35][C@H:36]([CH2:38][OH:41])[O:37][C:9]2=[O:8])[CH:16]=[CH:15][C:14]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[N:18]1
Reactant: CCOC(C)=O
Reactant: Cc1cn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)nn1
Reactant: CC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: Cc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)nn1

Procedure:
[3-Fluoro-4-(4-methyl-[1,2,3]-triazol-1-yl)-phenyl]-carbamic acid benzyl ester (Intermediate 20) (56 g, 0.17 mol), lithium hexamethyldisilazide (LiHMDS) (1M/THF, 200 ml, 0.20 mol) and R-(−)-glycidyl butyrate (25 ml, 0.18 mol) were reacted following the procedure described for Intermediate 25. Chromatography on silica gel with 0-40% acetone in ethyl acetate, followed by trituration with acetone/ethyl acetate/chloroform/hexanes (300 ml/100 ml/100 ml/500 ml) overnight gave the title compound as an off-white solid (33.9 g), m.p. 190.2-192.0° C.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].C(O)(=O)C.Cl[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].[Cl-].[K+]>C(O)C.O>[C:1]([O:4][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: O=C(CCl)c1ccccc1
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
78.5 g (0.80 mol) of potassium acetate, 5.0 g (0.08 mol) of acetic acid, and 123.7 g (0.80 mol) of 2-chloroacetophenone were heated under reflux in 500 mL of ethanol for 6 hours. After completion of heating, the reaction mixture was cooled to room temperature, deposited potassium chloride was filtered off, and the ethanol was distilled off in vacuo to obtain a pale brown oily material. This oily material was poured into one litter of water, and a precipitated solid was collected by filtration and recrystallized from methanol to obtain 113.1 g (yield: 79.3%) of 2-acetoxyacetophenone as a pale yellow solid.
Reaction SMILES: [CH:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].C(=O)([O-])O.[Na+].[CH2:23]([O:32][C:33](Cl)=[O:34])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CC(N(C)C)=O>[CH2:23]([O:32][C:33]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]2[OH:3])[C:11](=[O:12])[N:13]=1)=[O:34])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCOC(=O)Cl
Reactant: Nc1ccn(C2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
In 120 ml of dimethylacetamide, 6.0 g of arabinofuranosylcytosine is dissolved and to the resultant solution are added 4.15 g of sodium hydrogen carbonate and 7.66 g of nonyloxycarbonyl chloride. The mixture is then allowed to react under stirring at 20 to 25° C. for 2 hours. After the reaction, the solvent is removed under reduced pressure and the residue is dissolved in a small amount of ethanol. Water is then added to the resultant solution and the precipitated solids are collected by filtration, followed by drying. The white powders obtained are washed thoroughly with ethyl ether to obtain 3.8 g of N4 -nonyloxycarbonyl-1-β-D-arabinofuranosylcytosine (Yield:37%).
Reaction SMILES: Cl.[Si:2]([O:19][CH2:20][CH2:21]/[CH:22]=[CH:23]/[C@@H:24]([NH2:29])[CH2:25][CH:26]([CH3:28])[CH3:27])([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[C:37]1([P:43](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl.Cl>[Si:2]([O:19][CH2:20][CH2:21]/[CH:22]=[CH:23]/[C@@H:24]([NH:29][P:43]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:44])[CH2:25][CH:26]([CH3:27])[CH3:28])([C:15]([CH3:17])([CH3:18])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)C[C@H](N)/C=C/CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](/C=C/CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NP(=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 119.6 %

Procedure:
To a solution of the amine 7 (400 mg, 1.01 mmol) in dry DCM (7 mL) were added Et3N (0.44 mL, 3.13 mmol), and then a solution of diphenylphosphinic chloride (Ph2POCl, 0.22 mL, 1.11 mmol) in dry DCM (3 mL) at 0° C. After being stirred at 0° C. for 15 min, the reaction mixture was allowed to warm to rt and stirred for 4 h, then diluted with DCM and 10% HCl. The aqueous phase was extracted with DCM and the combined organic layers were washed with sat. NaHCO3, dried (MgSO4), filtered and concentrated in vacuo to afford 720 mg of the crude title compound as a pale yellow solidified oil, which was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[S:6].Cl[CH:12]([CH3:16])[C:13](=O)[CH3:14]>CCO.CCOC(C)=O>[CH3:16][C:12]1[N:7]=[C:5]([C:4]2[CH:3]=[C:2]([NH2:1])[CH:10]=[CH:9][CH:8]=2)[S:6][C:13]=1[CH3:14]
Reactant: CC(=O)C(C)Cl
Reactant: NC(=S)c1cccc(N)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(N)c2)sc1C
Temperature: 100 °C

Procedure:
To a solution of 3-amino-thiobenzamide (200 mg, 1.31 mmol, 1 eq.) in EtOH (4 mL) is added 3-chloro-2-butanone (140 mg, 1.31 mmol, 1 eq.). The mixture is heated at 100° C. for 72 h. After cooling to room temperature, the reaction is diluted with EtOAc and sequentially washed with saturated aqueous NaHCO3, H2O and saturated aqueous NaCl. The organic solution is dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (2:1 hexanes/EtOAc) to give 3-(4,5-Dimethyl-thiazol-2-yl)-phenylamine as a yellow oil. [MS: (ES+) 205.1 (M+1)+].
Reaction SMILES: CCN(CC)CC.[Cl-].[C:9]([C:12]1[C:39]([F:40])=[CH:38][C:15]2[NH:16][C:17]([C:19]3[CH:20]=[C:21]([C:26]4[C:27]([O:32][CH2:33][CH2:34][NH+:35]([CH3:37])[CH3:36])=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:22]=[CH:23][C:24]=3[OH:25])=[N:18][C:14]=2[CH:13]=1)(O)=[O:10].[NH2:41][CH2:42][CH2:43][C:44]1[N:48]=[CH:47][NH:46][CH:45]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:37][N:35]([CH3:36])[CH2:34][CH2:33][O:32][C:27]1[C:26]([C:21]2[CH:22]=[CH:23][C:24]([OH:25])=[C:19]([C:17]3[NH:16][C:15]4[CH:38]=[C:39]([F:40])[C:12]([C:9]([NH:41][CH2:42][CH2:43][C:44]5[NH:48][CH:47]=[N:46][CH:45]=5)=[O:10])=[CH:13][C:14]=4[N:18]=3)[CH:20]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: NCCc1c[nH]cn1
Reactant: C[NH+](C)CCOc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)O)c(F)cc3[nH]2)c1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCOc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)NCCc4cnc[nH]4)c(F)cc3[nH]2)c1
Yield: 53 %

Procedure:
Et3N (0.079 mL, 0.568 mmol, 8.0 eq.) was added to a mixture containing the crude carboxylic acid salt 9c (0.071 mmol, 1.0 eq.), histamine.2HCl (16 mg, 0.085 mmol, 1.2 eq.), EDC (15 mg, 0.078 mmol, 1.1 eq.) and HOBt (11 mg, 0.078 mmol, 1.1 eq.) in dry DMF (2 mL) and stirred for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography [10% (5% aq NH4OH/MeOH)/DCM] to afford the title compound (Rf=0.40) as a light yellow powder (20.1 mg, 53%). ES-MS MH+ 530.30.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH:20][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:7]=2)=[CH:16][CH:15]=1
Reactant: C=Cc1ccccc1
Reactant: Cc1ccc(CN)o1
Reactant: Clc1ccc2c(Br)cccc2n1
Product: Cc1ccc(CNc2ccc3c(/C=C/c4ccccc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=341.3 (M+H+), was prepared in accordance with the general method of example 2 from 5-bromo-2-chloroquinoline, 5-methyl-2-furanmethanamine and styrene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:18]2[CH:9]1[C:10]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:11]1[C:16]([CH2:17]2)=[CH:15][CH:14]=[C:13]([O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]1([CH3:41])C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-:49].[Na+]>C(O)C>[C:23]([O:22][C:20](=[O:21])[O:19][C:13]1[CH:14]=[CH:15][C:16]2[CH2:17][C@@H:18]([O:49][CH2:31][CH3:41])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:10]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:11]=2[CH:12]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CCC1(CC)c2cc(OC(=O)OC(C)(C)C)ccc2CC2C1N2C(=O)OC(C)(C)C
Reactant: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCO[C@@H]1Cc2ccc(OC(=O)OC(C)(C)C)cc2C(CC)(CC)[C@H]1NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
5-tert-Butoxycarbonyloxy-7,7-diethyl-1a,2,7,7a-tetrahydro-1-aza-cyclopropa[b]naphthalene-1-carboxylic acid tert-butyl ester (224.0 mg, 0.54 mmol) placed under Argon at room temperature was dissolved in anhydrous ethanol (8.0 mL). To this solution was added a catalytic amount of pyridinium p-toluene sulfonate. The reaction mixture was stirred overnight. The next day, the reaction mixture was poured into an aqueous solution of sodium bicarbonate and it was extracted using dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and the solvent was removed. The crude was purified by flash chromatography using; hexanes:ethyl acetate (9:1) then (8:2) as the eluent. The isolated product is a solid (129 mg, 55%).