Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[O:4]1[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]1.S(=O)(=O)(O)O.[CH2:22]([OH:27])[CH2:23][CH2:24][CH2:25][OH:26].[C:28](=O)([O-])[OH:29].[Na+]>O>[OH:26][CH2:25][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:4][CH2:5][CH2:28][OH:29].[CH2:22]([OH:27])[CH2:23][CH2:24][CH2:25][OH:26]
Reactant: O=C([O-])O
Reactant: CCCCCCCCCCC1CO1
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: OCCCCO
Solvent: O
Product: OCCCCCCCCCCCCOCCO
Temperature: 52.5 °C
Reaction time: 0.25 h
Yield: 94.1 %

Procedure:
Separately, a 100 ml mixing vessel equipped with a calcium chloride-containing tube was charged with 36.9 g (0.20 mole) of 1,2-epoxydodecane. While the charged 1,2-epoxydodecane was stirred and cooled with water, a concentrated sulfuric acid was gradually dropped in an amount of 0.4 g (0.004 mole) into the cooled 1,2-epoxydodecane. After stirring for 15 minutes, the resultant mixture was placed into the dropping apparatus attached to the reaction vessel and was dropped into 1,4-butanediol contained in the reaction vessel and maintained at a temperature of 50 to 55° C. over a time of 2 hours. Then the reaction of the mixture was carried out at a temperature of 50 to 55° C. for one hour. After the exhaustion of the starting material, namely 1,2-epoxydodecane, was confirmed by a thin-layer chromatography, the reaction was stopped. A saturated aqueous sodium hydrogen carbonate solution was mixed in an amount of 50 ml into the resultant reaction liquid in the reaction vessel, the resultant mixture was stirred for 10 minutes to neutralize the reaction liquid. The reaction liquid was subjected to an extraction procedure using diethyl ether to extract the reaction product. The resultant extraction liquid was concentrated by using a rotary evaporator. A 1,4-butanediol monohydroxydodecyl ether mixture was obtained in an amount of 50.4 g (yield: 94.1%).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:14]([N:21]1[CH2:11][C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=[CH:7][CH:6]=2)[C:3]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(Cl)cccc1CBr
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2c(Cl)cccc2CN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A mixture of 2-bromomethyl-6-chloro-benzoic acid methyl ester (0.132 g, 0.5 mmol), benzylamine (0.065 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-7-chloro-2,3-dihydro-isoindol-1-one (0.126 g, 99%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.22 (s, 2H), 4.76 (s, 2H) 7.28-7.46 (m, 8H). GC-MS: m/z 257 (M)+.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[C:15]([Cl:28])[N:14]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:17]3[CH:16]=[C:15]([Cl:28])[N:14]=[C:13]([Cl:12])[CH:18]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: CC1(C)OB(c2cc(Cl)nc(Cl)c2)OC1(C)C
Reactant: Clc1ccn2c(Br)cnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1ccn2c(-c3cc(Cl)nc(Cl)c3)cnc2c1

Procedure:
3-Bromo-7-chloro-imidazo[1,2-a]pyridine (1 eq, 3.02 mmol, 700 mg) and 2,6-dichloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (1.1 eq, 3.32 mmol, 1.01 g) are dissolved in DME (4 ml) and water (1 ml) and Na2CO3 (1.5 eq, 5.53 mmol, 562 mg) is added. PdCl2(PPh3)2 (0.1 eq, 0.3 mmol, 212 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 15 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield 7-chloro-3-(2,6-dichloro-pyridin-4-yl)-imidazo[1,2-a]pyridine as a yellow solid; [M+H]+=299
Reaction SMILES: Cl[C:2]1[N:26]=[CH:25][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.[CH3:27][C:28]1[CH:39]=[CH:38][CH:37]=[CH:36][C:29]=1[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.CN1C(=O)CCC1>C(N(CC)CC)C>[CH3:19][C:17]1[N:18]=[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:25]=[N:26][C:2]([N:32]5[CH2:33][CH2:34][CH2:35][CH:31]5[CH2:30][C:29]5[CH:36]=[CH:37][CH:38]=[CH:39][C:28]=5[CH3:27])=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)[N:15]([CH2:20][C:21]([F:24])([F:22])[F:23])[N:16]=1
Reactant: Cc1ccccc1CC1CCCN1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)n(CC(F)(F)F)n1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4CCCC4Cc4ccccc4C)cc2OCC3)n(CC(F)(F)F)n1
Temperature: 160 °C
Yield: 25.2 %

Procedure:
A 10 mL microwave vial was charged with 8-Chloro-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene (85 mg, 0.22 mmol) and 2-(2-Methyl-benzyl)-pyrrolidine (231 mg, 6 eq). 0.5 mL of NMP and 0.5 mL of triethylamine was added. The vial was sealed and heated at 160° C. for 24 h. After cooling to room temperature, the solution was purified directly by reverse phase HPLC (0.1% NH4OH/ACN). The isolated solid was further purified by chiral SFC (AD column, 35% MeOH isocratic) to give 27 mg of one enantiomer and 29 mg of 420 (48% total yield). LCMS: 524.2. 1H NMR (400 MHz, DMSO) δ 9.08 (s, 1H), 9.08 (s, 1H), 7.92 (s, 1H), 7.27-7.06 (m, 4H), 5.99 (s, 1H), 5.80 (q, J=8.9 Hz, 2H), 4.50 (m, 4H), 4.38 (br s, 1H), 3.49 (t, J=8.6 Hz, 1H), 3.15 (d, J=10.0 Hz, 1H), 2.60-2.53 (m, 1H), 2.42 (s, 3H), 2.28 (s, 3H), 2.10-1.89 (m, 2H), 1.81-1.71 (m, 2H)
Reaction SMILES: C(S)CC.C([Li])CCC.[CH2:10]([N:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][C@@H:14]1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:34])([CH3:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:22][C:21]=1[O:35]CC1C=CC=CC=1)[CH:11]=[CH2:12].C([S-])CC.[Li+]>O1CCCC1.CCCCCC.CN(C)P(N(C)C)(N(C)C)=O>[CH2:10]([N:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][C@@H:14]1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:34])([CH3:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:22][C:21]=1[OH:35])[CH:11]=[CH2:12]
Reactant: C=CCN1CC[C@H](O)C[C@@H]1c1ccc(C(C)(C)CCCCCC)cc1OCc1ccccc1
Agent: CCCS
Agent: CCC[S-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCN1CC[C@H](O)C[C@@H]1c1ccc(C(C)(C)CCCCCC)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
A solution of 6.8 ml (74.6 mmole) of propanethiol in 75 ml of tetrahydrofuran is degassed by three freeze-thaw cycles at 0.1 torr. The resultant solution is cooled to -78° C. and 28 ml of 2.5M n-butyllithium in hexane is added. The reaction is then allowed to warm to 25° C. and stirred 3 hours longer. The reaction is evaporated to dryness under high vacuum and the residue dissolved in 70 ml of degassed hexamethylphosphoramide. To a 25° C. degassed solution of 218 mg (0.486 mmole) of N-(2-propenyl)-cis-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinol in 1 ml of hexamethylphosphoramide is added 2.2 ml of the above prepared solution of lithium propanethiolate. The reaction is stirred 30 minutes at 25° C. and 1.5 hour at 105° C. followed by cooling to 25° C. The reaction is quenched by addition to 30 ml water and the mixture extracted with 150 ml ethyl ether. The ether extract is washed twice with 30 ml water, once with 30 ml saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The crude product is purified via column chromatography on 48 g of silica gel eluting in 8 ml fractions with ethyl ether to give (fractions 12-24) 101 mg (58%) of the title compound as an oil.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][C:8]1[S:9][CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>>[CH:1]1([C:4]([NH:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1ccsc1N
Product: COC(=O)c1ccsc1NC(=O)C1CC1

Procedure:
Cyclopropanecarbonyl chloride and methyl 2-aminothiophene-3-carboxylate (Aldrich) were processed using method analogous to that described in Example 13A to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[N:7]([CH3:11])[CH2:8][CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:16][CH:17]=[CH:18][N:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:12])[N:7]([CH2:8][CH2:9][N:23]1[CH2:24][CH2:25][N:20]([C:15]2[C:14]([Cl:13])=[N:19][CH:18]=[CH:17][N:16]=2)[CH2:21][CH2:22]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: Clc1nccnc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(CCN1CCN(c2nccnc2Cl)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add methyl-(2-oxo-ethyl)-carbamic acid t-butyl ester (27.69 mmoles; 4.80 g) and 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazine (25.17 mmoles; 5.00 g) to 1,2 dichloroethane (50.0 mL) on ice. Add sodium triacetoxyborohydride (32.7 mmoles; 6.93 g) in 3 portions. Stir the reaction mixture at room temperature overnight. Quench the reaction with water, separate the organic layer and concentrate. Wash in hexanes and filter to provide [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-carbamic acid t-butyl ester as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:22]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([O:14][C:13]([F:12])([F:24])[F:25])=[CH:16][CH:17]=3)=[O:23])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)Nc1ccc2ncccc2c1

Procedure:
Prepared from 6-aminoquinoline and 4-(trifluoromethoxy)phenyl isocyanate. m/z (ES+) 348 (M+H)+.
Reaction SMILES: [C:1]1([NH:11][C:12](=[S:15])[NH:13][NH2:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:16]OC(OC)N(C)C>O1CCOCC1>[C:1]1([N:11]2[CH:16]=[N:14][NH:13][C:12]2=[S:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(OC)N(C)C
Reactant: NNC(=S)Nc1cccc2ccccc12
Solvent: C1COCCO1
Product: S=c1[nH]ncn1-c1cccc2ccccc12
Yield: 100.2 %

Procedure:
A solution of 4-(1-naphthalenyl)-3-thiosemicarbazide (4.01 g, 18.4 mmol) and N,N,-dimethylformamide dimethyl acetal (2.50 mL, 18.8 mmol) in 1,4-dioxane (40 mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was taken in hexane and Et2O and the solution was stirred until a suspension was obtained. The suspension was filtered and the solid was triturated with hexane:Et2O (4:1), then was dried under reduced pressure to give the title compound (4.19 g, 90% yield) as a beige solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][C:7]1[C:15]2[C:14]([NH:16][C@H:17]([C:19]3[N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:23](=[O:31])[C:22]4=[C:32]([CH3:35])[CH:33]=[CH:34][N:21]4[N:20]=3)[CH3:18])=[N:13][CH:12]=[N:11][C:10]=2[N:9](COCC[Si](C)(C)C)[CH:8]=1.B(Br)(Br)Br.N>>[OH:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][C:7]1[C:15]2[C:14]([NH:16][C@H:17]([C:19]3[N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:23](=[O:31])[C:22]4=[C:32]([CH3:35])[CH:33]=[CH:34][N:21]4[N:20]=3)[CH3:18])=[N:13][CH:12]=[N:11][C:10]=2[NH:9][CH:8]=1
Reactant: COc1cccc(Cc2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Agent: BrB(Br)Br
Agent: N
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(Cc5cccc(O)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 81.4 %

Procedure:
(S)-2-(1-((5-(3-Methoxybenzyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (55 mg, 0.04 mmol) was treated with boron tribromide (1M in dichloromethane, 1.7 mL, 1.7 mmol) and a solution of ammonia (7N in methanol, 1 mL, 7 mmol) according to the method described in Example 41 to give 16 mg (75% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [H-].[Na+].[CH2:3]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])P(=O)(OCC)OCC.[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31](/[CH:32]=[CH:3]/[P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18])=[CH:34][CH:35]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C/c1ccc(OCc2ccccc2)cc1)OCC
Reaction time: 0.08 h
Yield: 98 %

Procedure:
To A 100 mL 2 necked RB flask charged with a suspension of NaH (0.14 g, 5.67 mmol) in THF (50 mL) under Nitrogen atmosphere was added tetraethyl methanediylbis(phosphonate) (1.63 g, 5.67 mmol) in THF drop wise at 0° C. This solution was stirred at the same temperature for 5 min followed by the addition of 4-(benzyloxy)benzaldehyde slowly. Reaction mixture was stirred at RT for 4 h. Excess NaH was quenched with ice and stirred for 5 min. Then the RM was diluted with ethyl acetate (50 mL) and the organic layer was washed with water (20 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as oil (1.6 g, yield: 98%). 1H NMR (300 MHz, CDCl3): δ 7.28-7.45 (m, 8H), 6.89-7.23 (d, 2H), 5.96-6.08 (t, 1H), 5.03 (s, 2H), 4.0-4.1 (m, 3H), 1.26-1.30 (t, 3H)
Reaction SMILES: O[CH:2]([C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][CH:11]=1)[CH:3]([CH3:9])[CH2:4][O:5][CH2:6][CH2:7][OH:8].[ClH:23].O.C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C>[Cl:23][CH:2]([C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][CH:11]=1)[CH:3]([CH3:9])[CH2:4][O:5][CH2:6][CH2:7][OH:8]
Reactant: Cl
Reactant: CC(COCCO)C(O)c1ccc(Cc2cccnc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(COCCO)C(Cl)c1ccc(Cc2cccnc2)cc1
Yield: 98 %

Procedure:
In 13.7 ml of ethanol was dissolved 2.74 g of 3-[p-[1-hydroxy-3-(2-hydroxyethyl)oxy-2-methylpropyl]benzyl]pyridine, and the resulting solution was saturated with hydrogen chloride with ice-cooling, after which the solution was subjected to reaction at room temperature for 2 hours. The solvent was removed by distillation under reduced pressure, and to the residue thus obtained were added 10 ml of water and 20 ml of ethyl acetate, after which the pH of the resulting mixture was adjusted to 7.0 with sodium hydrogencarbonate. The organic layer was separated, washed with 10 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 2.85 g (yield 98%) of colorless, oily 3-[p-[1-chloro-3-(2-hydroxyethyl)oxy-2-methylpropyl]benzyl]pyridine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:16][C:15]([NH:19][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13])([CH3:18])[CH3:17]
Reactant: CC(=O)c1ccccc1OCCCCl
Reactant: CC(C)(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccccc1OCCCNC(C)(C)C
Temperature: 120 °C
Reaction time: 19 h

Procedure:
A mixture of 2.58 g of the product of Step A, 8.3 ml of tert.-butylamine and 2.17 g of potassium carbonate in 7 ml of N,N-dimethylformamide was heated with stirring at 120° C. for 19 hours and was then diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried over a deshydrant and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 2.571 g of 1-[2-{3-(1,1-dimethylethylamino)-propoxy}-phenyl]-ethanone.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.Cl[C:10]1[C:11]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][S:18][C:12]=2[N:13]=[C:14]([CH2:16][Cl:17])[N:15]=1.C(N(CC)CC)C>C(O)C>[Cl:17][CH2:16][C:14]1[N:15]=[C:10]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]2)[C:11]2[C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:19][S:18][C:12]=2[N:13]=1
Reactant: ClCc1nc(Cl)c2c(-c3ccccc3)csc2n1
Reactant: OCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: OCC1CCN(c2nc(CCl)nc3scc(-c4ccccc4)c23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.8 %

Procedure:
4-Piperidinemethanol (0.85 g) was added to a suspension of 4-chloro-2-(chloromethyl)-5-phenyl-thieno[2,3-d]pyrimidine (1.45 g) in ethanol (70 mL). Triethylamine (1.4 mL) was added and the mixture was stirred at room temperature for 24 hr. The solvent was evaporated and the residue was dissolved in water (100 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (1×100 mL), dried (sodium sulfate), filtered and evaporated to give an off-white foam (1.76 g). This was purified by silica chromatography (50 g cartridge; eluent petroleum ether 40-60/ethyl acetate 0 to 50%; collection by UV trigger). Fractions corresponding to the main peak were combined and evaporated to give the target compound as a white foam (1.10 g). m/z [M+H]+373.9/375.9. Retention time 4.67 min (LCMS method+ve 6 min).
Reaction SMILES: C([S:9][C:10]1[S:11][C:12]2[CH2:18][NH:17][CH:16]([C:19](OC(C)(C)C)=O)[CH2:15][C:13]=2[N:14]=1)(=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C=O.[OH-].[Na+].C([BH3-])#N.[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[SH:9][C:10]1[S:11][C:12]2[CH2:18][NH:17][CH:16]([CH3:19])[CH2:15][C:13]=2[N:14]=1
Reactant: CC(C)(C)OC(=O)C1Cc2nc(SC(=O)c3ccccc3)sc2CN1
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: COc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1Cc2nc(S)sc2CN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To 2-benzoylthio-6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydropyrido[4,3-d][1,3]thiazole (2.44 g, 6.49 mmol) is gradually added dropwise a mixture of anisole (1.41 ml, 12.98 mmol) and trifluoroacetic acid (10.0 ml, 129.8 mmol) at 0° C., and after the addition, the mixture is warmed to room temperature and stirred for 30 minutes. The reaction solution is concentrated under reduced pressure, and to the resulting residue is added methylene chloride. The mixture is concentrated under reduced pressure again, and the resulting residue is crystallized from ether to give pale yellow crystals. The resulting crystals are suspended in THF (30 ml), and thereto is added a 37% aqueous formaldehyde solution (2.04 g, 25.2 mmol) at room temperature, and then further added thereto a 2N aqueous sodium hydroxide solution. The mixture is stirred for one hour, and thereto is added sodium cyanoborohydride (507 mg, 8.06 mmol), and the mixture is further stirred for additional one hour. To the reaction solution is added iN aqueous hydrochloric acid solution to make it weakly acidic, and the mixture is stirred for 30 minutes. The reaction solution is diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (methylene chloride/methanol=20˜10) to give 2-mercapto-6-methyl-4,5,6,7-tetrahydropyrido[4,3-d][1,3]thiazole (525 mg, yield; 44%) as pale yellow amorphous.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[O:17]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18]1.C(=O)([O-])[O-].[K+].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[O:17]1[CH:21]=[CH:20][C:19]([C:2]2[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=2)=[CH:18]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccoc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2ccoc2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a mixture of tert-butyl N-(4-bromobenzyl)carbamate (0.14 g), 2-(furan-3-yl)-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (0.12 g), potassium carbonate (0.1 g), water (0.2 mL) and N,N-dimethylformamide (1 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.03 g), and the resulting mixture was stirred at 80° C. for 12 hours. The reaction mixture was cooled to room temperature and then the insoluble material was filtered out. The filtrate was partitioned between ethyl acetate (110 mL) and water (50 mL). The organic layer was washed successively with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on aminopropylated silica gel (eluent: hexane/ethyl acetate=1/1) to give tert-butyl N-[4-(furan-3-yl)benzyl]-carbamate. The compound obtained was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.57 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate (15 mL) was added dropwise and the whole was extracted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate/brine (1/1, 10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.06 g).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[C:5](=O)[C:4]1=[O:14])[CH3:2].O.NN>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[CH2:5][C:4]1=[O:14])[CH3:2]
Reactant: CCN1C(=O)C(=O)c2cccc(F)c21
Agent: NN
Solvent: O
Product: CCN1C(=O)Cc2cccc(F)c21
Temperature: 0 °C

Procedure:
1-Ethyl-7-fluoro-1H-indole-2,3-dione (3.60 g, 18.6 mmol) is heated with neat hydrazine hydrate (15 ml) at 130° C. for 60 minutes. The mixture is cooled, diluted with ice water and extracted with ethyl acetate. The extract is washed with brine, dried (Na2SO4), and evaporated to give the title compound as an orange solid. HPLC r.t. 4.60 min; MS for C10H10FNO m/z 198.1 (M+H)+.