Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[CH3:18])[C@H:5]([OH:19])[C@@H:4]1[OH:20].[CH3:21][S-:22].[Na+]>CN(C=O)C>[CH3:21][S:22][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[CH3:18])[C@H:5]([OH:19])[C@@H:4]1[OH:20]
Reactant: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
A solution of 3a (200 mg, 0.66 mmol) and sodium thiomethoxide (47 mg, 0.67 mmol) in 2 mL of anhydrous DMF was stirred for 2 days at room temperature and then concentrated to dryness. The crude product was purified by column chromatography using chloroform:methanol (7:1) as eluent. The desired fractions were collected, concentrated and dried in vacuo: yield 102 mg (49%); MS m/z 312 (M+H)+; 1HNMR (DMSO-d6) δ 8.09 (s, 1H, H-2), 7.12 (bs, 2H, 6-NH2), 5.77 (d, 1H, H-1′, J1′,2′=5.7 Hz), 5.38 (bd, 1H, OH-2′, J2′-2′OH=4.4 Hz), 5.31 (d, 1H, OH-3′, J3′-3′OH=4.2 Hz), 5.15 (bddd, 1H, H-2′, J1′,2′=5.7 Hz, J2′,3′=5.7 Hz, J2′-2′OH=4.4 Hz), 4.20 (ddd, 1H, H-3′, J2′,3′=5.7 Hz, J3′,4′=3.6 Hz, J3′-3′OH=4.2 Hz), 3.97-4.05 (m, 1H, H-4′), 2.74-2.92 (m, 2H, 5′-CH2), 2.54 (s, 3H, 8-CH3), 2.03 (s, 3H, S—CH3).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[Cl:8][C:7]1[C:2]([NH:10][NH2:11])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: NNc1ncccc1Cl
Yield: 89.4 %

Procedure:
To 30 ml of an n-butanol solution containing 7.0 g of 2,3-dichloropyridine were added 7.1 g of hydrazine monohydrate and 6.54 g of anhydrous potassium carbonate, and the mixture was heated under reflux for 17.5 hours. After cooling, the precipitate was collected by filtration to yield 6.07 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:32])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11]([Cl:32])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1cc(C(=O)Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2,4-Bis-benzyloxy-5-isopropyl-benzoic acid (Preparation B10) (0.2 g, 0.53 mmol) was dissolved in DCM (10 ml) and treated with oxalyl chloride (1.5 g, 12 mmol) and a catalytic amount of DMF. The reaction mixture was stirred at room temperature for 14 hours and the solvent was then removed in vacuo. The crude material was dissolved in toluene and evaporated. Crude 2,4-bis-benzyloxy-5-isopropyl-benzoyl chloride was obtained as an oil (200 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](=[O:27])[N:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[O:23][CH:24]=[CH:25][N:26]=4)[CH:17]=3)[N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:28]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1>[Br:28][C:24]1[O:23][C:22]([C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=2)[CH2:15][N:13]2[C:12](=[O:27])[CH:11]=[CH:10][C:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)=[N:14]2)=[N:26][CH:25]=1
Reactant: O=c1ccc(-c2cc(F)cc(F)c2)nn1Cc1cccc(-c2ncco2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: O=c1ccc(-c2cc(F)cc(F)c2)nn1Cc1cccc(-c2ncc(Br)o2)c1

Procedure:
A solution of 184 mg (0.504 mmol) of 6-(3,5-difluorophenyl)-2-(3-oxazol-2-ylbenzyl)-2H-pyridazin-3-one, 108 mg (0.605 mmol) of N-bromosuccinimide and 6.3 mg (0.026 mmol) of benzoyl peroxide in 1 ml of chlorobenzene is stirred at 80° C. for 42 hours. The reaction mixture is evaporated and chromatographed on a silica-gel column with dichloromethane/methanol as eluent, giving 2-[3-(5-bromooxazol-2-yl)benzyl]-6-(3,5-difluorophenyl)-2H-pyridazin-3-one as yellowish crystals; ESI 444, 446.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:22]([N:24]2[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]2)[CH3:23])[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH:22]([N:24]2[CH2:25][CH2:26][CH:27]([NH:30][C:2]3[C:3]4[CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:28][CH2:29]2)[CH3:23])[CH:19]=[CH:20][CH:21]=1
Reactant: CC(c1cccc(F)c1)N1CCC(N)CC1
Reactant: CC(C)Cc1cc2c(Cl)ncnc2s1
Product: CC(C)Cc1cc2c(NC3CCN(C(C)c4cccc(F)c4)CC3)ncnc2s1

Procedure:
The title compound was prepared (291 mg, 64%) from 4-chloro-6-isobutylthieno[2,3-d]pyrimidine (250 mg, 1.1 mmol) and 1-(1-(3-fluorophenyl)ethyl)piperidin-4-amine (0.49 mg, 2.2 mmol) by following the general procedure described for Preparation 6. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.25 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 6.75 (s, 1H), 5.00 (m, 1H), 4.10 (m, 1H), 3.45 (m, 1H), 3.00 (d, 1H), 2.80 (d, 1H), 2.70 (d, 2H), 1.85-2.25 (m, 5H), 1.45-1.65 (m, 2H), 1.35 (d, 3H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 412.57; Observed: 413.3 (M++1).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23](Cl)=[N:24][CH:25]=[N:26]2)=[CH:21][C:20]=1[O:30][CH3:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN1CCCC1=O>[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[N:24][CH:25]=[N:26]2)=[CH:21][C:20]=1[O:30][CH3:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Sodium hydride (400 mg of an 80% suspension in paraffin oil, 13.3 mmol) was added to a solution of phenol (1.26 g, 13.3 mmol) in dry N-methylpyrrolidone (20 ml) and the mixture stirred for 10 minutes. 7-Benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.6 g, 4.7 mmol), (prepared as described for the starting material in Example 1), was then added and the reaction mixture heated at 110° C. for 2 hours. The mixture was allowed to cool, water was added and the mixture extracted with ethyl acetate (3×100 ml). The combined extracts were then washed with 2M sodium hydroxide solution, water and brine. Removal of the solvent under reduced pressure gave 7-benzyloxy-6-methoxy-4-phenoxyquinazoline (1.6 g, 95%) as a yellowish solid.
Reaction SMILES: [O:1]=[P:2]12[O:13]P3(OP(OP(O3)([O:9]1)=O)(=O)[O:3]2)=O.C[Si](C)(C)O[Si](C)(C)C.[CH2:24]([S:36][CH2:37][CH:38]([O:41][CH2:42][CH2:43][CH2:44]CCCCCCC)[CH2:39]O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>N1C=CC=CC=1>[CH2:24]([S:36][CH:37]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:38]([O:41][CH2:42][CH2:43][CH2:44][O:3][P:2](=[O:1])([OH:13])[OH:9])[CH3:39])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Reactant: CCCCCCCCCCCCSCC(CO)OCCCCCCCCCC
Solvent: c1ccncc1
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: CCCCCCCCCCCCSC(CCCCCCC)C(C)OCCCOP(=O)(O)O
Temperature: 100 °C

Procedure:
A suspension of 4.26 g P4O10 in 60 ml absolute pyridine was admixed at room temperature with 13 ml hexamethyldisiloxane and heated to 100° C. for 1 hour. It was then slightly cooled, admixed with 25 g 3-dodecylmercapto-2-decyloxy-1-propanol and heated for a further 2.5 hours to 100° C.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13].[OH-].[Na+]>O>[C:3]1([CH3:8])[CH:4]=[CH:5][C:6]([O:7][CH2:10][CH2:11][CH2:12][Cl:13])=[CH:1][CH:2]=1
Reactant: ClCCCBr
Reactant: Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(OCCCCl)cc1
Temperature: 0 °C
Yield: 76.7 %

Procedure:
3.0 g of p-cresol and 4.0 g of 3-bromo-1-chloro propane were placed into 20 ml of water and were subjected to reflux for 1 hour under heating, and whereto 20 ml of the aqueous solution of sodium hydroxide containing 1.2 g of sodium hydroxide were fed dropwise. After subjecting the resultant solution prepared as described hereinabove to reflux for another 2 hours, the solution reacted was poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer resulted was washed with dilute aqueous alkaline solution and saturated saline solution in series, and the organic layer resulted was then dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduce pressure, thereby affording 3.6 g of 3-(4-tolyloxy)-1-chloro propane.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[CH3:29][CH:30]([CH3:50])[C:31](=[O:49])[CH2:32][NH:33][C:34]([CH2:36][CH2:37][NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=O>ClCCl>[CH:30]([C:31]1[O:49][C:34]([CH2:36][CH2:37][NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[N:33][CH:32]=1)([CH3:50])[CH3:29]
Reactant: CC(C)C(=O)CNC(=O)CCNC(=O)OCc1ccccc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cnc(CCNC(=O)OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
100.00 g (215 mmol) PS-triphenylphosphine are suspended in 1000 ml dichloromethane, 59.92 g (236.06 mmol) iodine are added. The mixture is stirred for 0.1 hours at ambient temperature, then 65.32 ml (470.24 mmol) triethylamine are added dropwise. 28.80 g (94.91 mmol) benzyl [2-(3-methyl-2-oxo-butylcarbamoyl)-ethyl]-carbamate dissolved in 200 ml dichloromethane are added. The reaction mixture is stirred for 16 hours at ambient temperature. If the reaction is incomplete, a further 0.1 eq triphenylphosphine and 0.1 eq iodine are added. The mixture is stirred for 16 hours at ambient temperature, then the precipitate is filtered off. The filtrate is evaporated down, the residue is extracted with water and chloroform, the organic phase is dried and evaporated to dryness. The residue is purified by chromatography.
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]([S:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[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.CN(C)C(N(C)C)=N.[F:36][C:37]([F:44])([F:43])[C:38](OCC)=[O:39]>CO>[F:36][C:37]([F:44])([F:43])[C:38]([NH:21][C@@H:19]([CH3:20])[C@H:18]([S:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:39]
Reactant: C[C@H](N)[C@H](Sc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: CCOC(=O)C(F)(F)F
Agent: CN(C)C(=N)N(C)C
Solvent: CO
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](Sc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
To (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-ylthio)-1-phenylpropan-2-amine (0.024 g, 0.06 mmol) in MeOH (2.5 mL), 1,1,3,3-tetramethylguanidine (0.056 mL, 0.45 mmol) and ethyl trifluoroacetate (0.114 mL, 0.95 mmol) was added and the mixture was stirred at rt O/N and than submitted to purification on HPLC. The relevant fractions were collected freezdried to give 16 mg of product (53% yield) which was analysed by LC/MS and NMR.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([C:38]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[O:39])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: O=C(Cl)N1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(C3CCN(C(=O)N4CCOCC4)C3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
(5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (75 mg, 0.183 mmol) was dissolved in tetrahydrofuran (2 mL). Morpholine-4-carbonyl chloride (27 mg, 0.183 mmol) was added to the reaction mixture followed by triethylamine (51 uL, 0.366 mmol). The suspension was stirred at rt overnight. The reaction was concentrated under vacuum. The compound was triturated with 1:1 ether-hexanes to yield desired product (70 mg, 73%). 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.92 (s, 1 H), 7.79 (d, 1 H), 7.58 (m, 3 H), 7.35-7.32 (m, 4 H), 7.13 (d, 1 H), 6.67 (s, 1 H), 5.64 (s, 2 H), 3.90-2.50 (m, 13 H), 2.50-2.10 (m, 2 H); ES-MS m/z 523.3 [M+H]+, HPLC RT (min) 2.47.
Reaction SMILES: [F:1][C:2]1([F:18])[C:7]([F:9])([F:8])[O:6][C:5]([F:11])([F:10])[C:4](F)(F)[N:3]1[C:14]([F:17])([F:16])[F:15].S(=O)(=O)=[O:20].S(=O)(=O)(O)O.FC1(F)OC(F)(F)C(=O)N(C(F)(F)F)C1=O>>[F:10][C:5]1([F:11])[O:6][C:7]([F:9])([F:8])[C:2]([F:18])([F:1])[N:3]([C:14]([F:17])([F:16])[F:15])[C:4]1=[O:20]
Reactant: FC(F)(F)N1C(F)(F)C(F)(F)OC(F)(F)C1(F)F
Reactant: O=S(=O)=O
Agent: O=C1N(C(F)(F)F)C(=O)C(F)(F)OC1(F)F
Agent: O=S(=O)(O)O
Product: O=C1N(C(F)(F)F)C(F)(F)C(F)(F)OC1(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 253 g. (0.85 mol) of perfluoro-(N-methyl-morpholine) in a 300 ml. autoclave is added 72 g. (0.9 mol) of sulfur trioxide. The vessel is sealed, heated and rocked at 120° C. for 6 hrs. The autoclave is then cooled to 25° C., vented to release volatile materials and the residue charged to a 500 cc. flask equipped with magnetic stirrer, dropping funnel, condenser and thermometer. A solution of 195 g. of 96% sulfuric acid and 5 g. of H2C is added dropwise with stirring. The temperature is kept below 50° C. After the sulfuric acid is added the mixture is heated and stirred at reflux (55°-60° C.) for four hours. Distillation yields a large fraction, 207 g., b.p. 48°-65° C./740 mm., which consists of 45% by weight perfluoror-N-methyl-3-oxo-morpholine (40% conversion) and 15% by weight of higher boiling products believed to include perfluoro-(N-methyl-3,5dioxo-morpholine). Isolation of the pure amide (b.p. 59°-60° C./740 mm.) can be accomplished by distillation through a 25-plate column.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[S:4][CH2:3]1.[CH2:20]([O:22][C:23](=[O:34])[C:24](=O)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:21].C([BH3-])#N.[Na+]>>[CH2:20]([O:22][C:23]([CH:24]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]2[CH2:16][CH:17]=[CH:18][CH:19]=[C:5]2[S:4][CH2:3]1)[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:34])[CH3:21]
Reactant: CCOC(=O)CN1C(=O)C(N)CSc2ccccc21
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCC)CSC2=CC=CCC21

Procedure:
(±)-3-Amino-3,4-dihydro-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester is reacted with ethyl-2-oxo-4-phenylbutyrate in the presence of sodium cyanoborohydride according to the procedure of Example 1(f) to yield (±)-dihydro-3-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:9])[CH:8]=1)N.BrC1C=C([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[C:7]([Br:9])[CH:8]=1
Reactant: Brc1cccc(-c2cccs2)c1
Reactant: Nc1cc(Br)cc(Br)c1
Product: Brc1cc(Br)cc(-c2cccs2)c1
Yield: 55 %

Procedure:
3,5-dibromoaniline was treated as described in the procedure for 2-(3'-bromophenyl)thiophene to give 2-(3',5'-dibromophenyl)thiophene in 55% yield as a yellow oil, which solidified as a glassy solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[N:11]1([CH2:16][CH2:17]O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:17][CH2:16][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: OCCN1CCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(OCCN2CCCC2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (555 mg) were added 2-pyrrolidine-1-yl-ethanol (0.3 mL), PPh3 (721 mg), and DEAD (0.43 mL). The mixture was stirred room temperature for 16 h. The reaction mixture was concentrated. The residue was treated with Et2O, filtered and the filtrated was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, EtOAc:Hexane=10:80 to 80:20) to give 1-[2-(4-bromo-3,5-dimethyl-phenoxy)-ethyl]-pyrrolidine as a white solid: MS (m/z) 300 (M+1).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH:24]=[CH:25][C:26](=[O:28])[CH3:27]>C(O)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH:24]1[CH2:3][C:2](=[O:1])[CH2:27][C:26](=[O:28])[CH2:25]1
Reactant: CC[O-]
Reactant: CC(=O)C=Cc1cc(F)ccc1F
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC(=O)OCC
Product: O=C1CC(=O)CC(c2cc(F)ccc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 20% solution of sodium ethoxide in ethanol (27.7 g) was combined at room temperature with diethyl malonate (13.0 g) and then with 4-(2,5-difluorophenyl)-3-buten-2-one (13.8 g) in portions. The reaction mixture was stirred at room temperature for 30 minutes and then heated with stirring for 2 hours. After allowing to stand to cool, the solvent was distilled off, and the residue was combined with water, and the aqueous layer was washed with ethyl acetate and concentrated. 2N Sodium hydroxide (42 ml) was added and the mixture was heated under reflux for 2 hours. After allowing to stand to cool, 2.5 M sulfuric acid (42 ml) was added over a period of 10 minutes, and then the mixture was heated under reflux for 3 hours. After allowing to stand to cool, the precipitated crystal was recovered by a filtration and washed successively with water and isopropyl ether to obtain 5-(2,5-difluorophenyl)cyclohexane-1,3-dione (11.6 g) as a colorless crystal.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:27]=[CH:26][C:22]2[NH:23][N:24]=[N:25][C:21]=2[CH:20]=1>C1(C)C(C)=CC=CC=1>[C:2]1([C:1]2([N:23]3[C:22]4[CH:26]=[CH:27][C:19]([Br:18])=[CH:20][C:21]=4[N:25]=[N:24]3)[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:13])[O:8]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc2[nH]nnc2c1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Solvent: Cc1ccccc1C
Product: O=C1OC(c2ccccc2)(n2nnc3cc(Br)ccc32)c2ccccc21

Procedure:
10.0 g (0.04 mol.) of commercial 2-benzoylbenzoic acid and 7.8 g (0.04 mol.) of 5-bromobenzotriazole were added to 300 ml of dried xylene, and refluxed for 8 hours as heat was applied thereto by means of the dehydration-reflexing apparatus. After cooling, the insoluble material was filtered off with suction, and the filtrate was concentrated to obtain 12.4 g of oily substance. This oily substance was separated and purified by flash column chromatography (silica gel: 400 g, eluate: hexane-ethyl acetate (3:2 by volume) mixture) to obtain the intended compound, 3-phenyl-3-(5-bromo-1-benzotriazolyl)phthalide (22), in the form of white crystals. Yield 8.1 g, Melting Point 128° to 131° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15](Cl)=[O:16])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:18]1([NH2:27])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=[CH:19]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[N:18]1([NH:27][C:15]([C:11]2[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:16])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=[CH:19]1
Reactant: Nn1ccc2cccnc21
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid chloride (1 mmol) in EtOAc (10 mL) is added to a stirred solution of pyrrolo[2,3-b]pyridin-1-ylamine (1 mmol) and K2CO3 (1 mmol) in EtOAc (20 mL) and H2O (20 mL) at rt, then stirred at rt overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration. The solid is purified by silica gel chromatography eluting with 20-80% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid pyrrolo[2,3-b]pyridin-1-ylamide (162 mg, 47%) as a solid. MS: 348 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.78 (s, 3H), 6.59 (m, H) 7.09-7.58 (m, 4H), 7.96 (m, H), 8.22 (m, H), 8.31 (d, 2H), 9.14 (s, 2H). IC50=12 nM.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[O-]CC.[Na+].Cl>C(O)C>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]([C:4]([OH:3])=[O:5])=[C:10](/[CH:11]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:9][N:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)noc1C
Reactant: O=Cc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1c(-c2ccc(F)cc2)noc1/C=C/c1ccccc1
Yield: 77 %

Procedure:
To a solution of 3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (20.0 g, 80.2 mmol) and benzaldehyde (8.19 mL, 80.2 mmol) in ethanol (113 mL) was added sodium ethoxide (2.71 M, 32.5 mL, 88.3 mmol) and the reaction mixture was heated under reflux for 1 h. Hydrochloric acid (1 N, 96.3 mL) was added and the resulting mixture was extracted with toluene. The solvent was then distilled off to afford the title compound (19.1 g, 77%) as a light yellow solid. MS: m/e=308.0 [M−H]−.
Reaction SMILES: [F:1][C:2]1[C:19](F)=[CH:18][C:17]2[C:16](=[O:21])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:22])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:29]([O:36][CH3:37])(=[O:35])[CH2:30][C:31]([O:33][CH3:34])=[O:32].Cl>CS(C)=O>[F:1][C:2]1[CH:19]=[C:18]([CH:30]([C:29]([O:36][CH3:37])=[O:35])[C:31]([O:33][CH3:34])=[O:32])[C:17]2[C:16](=[O:21])[C:15]3[C:6]([C:5](=[O:22])[C:4]=2[CH:3]=1)=[CH:7][C:8]1[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:14]=3
Reactant: COC(=O)CC(=O)OC
Reactant: O=C1c2cc(F)c(F)cc2C(=O)c2cc3ccccc3cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1cc(F)cc2c1C(=O)c1cc3ccccc3cc1C2=O

Procedure:
1 g (3.4 mmol) of 2,3-difluoro-naphthacene-5,12-dione, 0.94 g (6.8 mmol) of potassium carbonate, 0.89 g (6.8 mmol) of dimethyl malonate and 20 ml of DMSO are stirred at 50° C. for 22 hours. The mixture is poured onto dilute hydrochloric acid and extracted with THF/toluene. The organic phase is washed with water, dried over sodium sulfate and evaporated. The product is purified by chromatography over silica gel (mobile phase: 1% acetone/99% CH2Cl2); yield 1.25 g (91%); melting point 225°-230° C.