Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([SH:7])[CH2:5][CH3:6].Cl[C:9]1[C:14]([CH2:15][CH3:16])=[N:13][C:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])=[C:11]([CH2:27][CH3:28])[N:10]=1>C1COCC1>[CH:4]([S:7][C:9]1[C:14]([CH2:15][CH3:16])=[N:13][C:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])=[C:11]([CH2:27][CH3:28])[N:10]=1)([CH2:5][CH3:6])[CH3:3]
Reactant: CCC(C)S
Reactant: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1SC(C)CC
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
NaH (60 mg, 1.5 mmol. 60% in mineral oil) is added to a solution of butane-2-thiol (170 μL, 1.5 mmol) in THF (5 mL). After 10 minutes, 2-chloro-5-(2,4-dimethoxy-phenyl)-3,6-diethyl-pyrazine (100 mg, 0.33 mmol) in THF (1 mL) is added dropwise, and the mixture heated at 80° C. (oil bath temperature) for 16 hours. After extractive work-up, preparative thin layer chromatography (hexanes) furnishes the title compound as a clear oil (60 mg, 51%). NMR (CDCl3, 400 MHz) H-1: 7.19 (1H, d, J=8.4 Hz), 6.58 (1H, dd, J=2.4, 8.4 Hz), 6.60 (s, 1H, J=2.4 Hz), 3.99 (sext, 1H, J=6.8 Hz), 3.85 (3H, s), 3.75 (3H, s), 2.81 (2H, q, J=7.4 Hz), 2.58 (2H, br q, J=6.8 Hz), 1.6–1.9 (m, 4H), 1.44 (3H, d, J=6.4 Hz), 1.28 (t, 3H, J=7.6 Hz), 1.19 (3H, t, J=7.6 Hz), 1.06 (t, 3H, J=7.2 Hz). C-13: 161.10, 157.86, 153.49, 151.79, 151.67, 144.47, 131.68, 121.18, 104.78, 98, 60, 55.44, 55.33, 40.87, 29.65, 27.54, 27.08, 20.56, 12.43, 12.09, 11.51. MS: 414.2 (+1, positive mode) and 412.2 (M−1, negative mode).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22]O)=[C:14]([Br:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:45]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][Br:45])=[C:14]([Br:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(CO)nc3N21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(CBr)nc3N21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.400 g (4R,9aR)-7-bromo-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 21 step 1) in 5 ml dichloromethane was added at room temperature 0.4 g triphenylphosphine and carbontetrabromide and the mixture was stirred at room temperature for 30 min. The red-orange solution was purified by chromatography on silica gel with heptane:ethyl acetate=1:1. The product fractions were collected and evaporated. The resulting oil (showing crystal seeds) was triturated with hexane. The crystalline solid was collected and dried to constant weight to yield 0.307 g of the title compound (MS: 406.1; 404.2 (M+H+)).
Reaction SMILES: O[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:12][C:13]=2[CH3:14])=[C:5]([O:24][CH3:25])[CH:4]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:35])=O>C(OCC)(=O)C>[Cl:35][CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:12][C:13]=2[CH3:14])=[C:5]([O:24][CH3:25])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)/C=C/c1nc(COc2ccc(CO)cc2OC)c(C)o1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1nc(COc2ccc(CCl)cc2OC)c(C)o1
Yield: 89.1 %

Procedure:
To mixture of ethyl (2E)-3-{4[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (5.0 g) and toluene (100 mL) was added thionyl chloride (1.88 g), and the mixture was heated under reflux for 1 hr. After concentration of the reaction mixture, ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl(2E)-3-{4[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (4.69 g, yield 89%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 107-108° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:26][S:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]=[CH:38][C:39](=[NH:41])[NH2:40])=[CH:33][CH:32]=1)(=[O:29])=[O:28]>N1C=CC=CC=1>[CH3:26][S:27]([OH:30])(=[O:29])=[O:28].[C:1]1([CH2:7][C:8]([O:10][C:31]2[CH:36]=[CH:35][C:34]([CH:37]=[CH:38][C:39](=[NH:40])[NH2:41])=[CH:33][CH:32]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CS(=O)(=O)Oc1ccc(C=CC(=N)N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CS(=O)(=O)O
Product: N=C(N)C=Cc1ccc(OC(=O)Cc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
To a solution of 1.4 g of phenylacetic acid in 50 ml of dried pyridine, was added 3.1 g of DCC. After 30 minutes of stirring, 2.6 g of 4-(β-amidinoethenyl)phenol methanesulfonate was added to the mixture and stirred overnight. The insolubles were removed by filtration and ethyl ether was added to the filtrate to precipitate crystals. The crystals were collected by filtration and recrystallized from ethanol to obtain 1.5 g of 4-(β-amidinoethenyl)phenyl phenylacetate methanesulfonate.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11](Cl)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])[CH3:18].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH2:17]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:11]2[N:10]=[N:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:13]([CH3:14])[C:12]=2[CH3:15])[CH2:24][CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1c(Cl)nnc(Cc2ccccc2)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCN(c2nnc(Cc3ccccc3)c(C)c2C)CC1
Temperature: 210 °C
Yield: 61.7 %

Procedure:
To a solution of 3-benzyl-6-chloro-4,5-dimethyl-pyridazine (1.0 g, 4.31 mmol) in NMP (10 mL) is added piperidine-4-carboxylic acid ethyl ester (2.0 g, 12.9 mmol) and DIPEA (3.7 mL, 21.6 mmol). The mixture is heated in microwave at 210° C. for 1.5 h. The mixture is concentrated at 80° C. by rotovaporation. The crude product is purified by HPLC (CH3CN/H2O: 22%˜45% with 0.1% TFA) to give 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid ethyl ester (0.94 g, 61%).
Reaction SMILES: O[NH:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][C:5]=1[OH:12].CN(C)C=O.S(Cl)([Cl:21])=O>C(Cl)Cl>[Cl:21][CH2:10][C:7]1[CH:8]=[CH:9][C:4]2[C:3]([OH:13])=[N:2][O:12][C:5]=2[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(NO)c1ccc(CO)cc1O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Oc1noc2cc(CCl)ccc12
Reaction time: 2 h

Procedure:
In 50 mL of methylene chloride was suspended 10.0 g of N,2-dihydroxy-4-(hydroxymethyl)benzamide. To this, 0.21 mL of N,N-dimethylformamide was added. This was cooled and 8.36 mL of thionyl chloride was added dropwise under ice-cooling. After 2 hours of stirring under heating reflux, 13 mL of solvent was distilled off under atmospheric pressure. To the reaction mixture was added 13 mL of methylene chloride, 4.64 mL of pyridine was added dropwise at 20-30° C., and the results were stirred for 1 hour at the same temperature. After adding 20 mL of water and 50 mL of acetone, 50 mL of solvent was distilled off under atmospheric pressure, solids were filtered, and 6.45 g of 6-(chloromethyl)-1,2-benzisoxazol-3-ol in the form of a pale yellowish-white solid was obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C@H:14]([C@@:20]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)([NH:22][CH:23]([CH3:25])[CH3:24])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=O)[CH:11]=[CH:12][CH:13]=1.CN(C=O)C>C1C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[C@:20]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:21])[N:22]([CH:23]([CH3:24])[CH3:25])[C:17](=[O:19])[CH2:16][CH2:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)N[C@](C)(c1ccc(Cl)cc1)[C@H](CCC(=O)O)c1cccc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@@]1(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Oxalyl chloride (˜0.38 M in benzene, 0.617 mL, 0.234 mmol) was added to a room temperature solution of (4R,5S)-4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-(isopropylamino)hexanoic acid (Example 418, Step G, 84 mg, 0.213 mmol) in benzene (3 mL) followed by a drop of DMF. The reaction solution was stirred at room temperature for 25 minutes then heated to 80° C. After 3.5 hours the reaction was removed from heat and saturated aqueous sodium bicarbonate solution was added. The organic phase was diluted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, then dried with anhydrous magnesium sulfate and concentrated to afford a red-orange oil. The product was isolated by chromatography on silica (12 g RediSep Rf cartridge) eluting with 20-40% ethyl acetate gradient in hexane to afford the title compound as a pale yellow film. [α]D=+89.33° (T=24.0° C.; c=1, CHCl3)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:23]([F:24])=[CH:22][C:14]([C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])=[C:13]([F:25])[CH:12]=2)[CH:5]=[N:6][C:7]=1F.[F:26][C:27]([F:33])([F:32])[C:28]([CH3:31])([OH:30])[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:23]([F:24])=[CH:22][C:14]([C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])=[C:13]([F:25])[CH:12]=2)[CH:5]=[N:6][C:7]=1[O:30][C:28]([CH3:31])([CH3:29])[C:27]([F:33])([F:32])[F:26]
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(COc2cnc(F)c(Cl)c2)cc1F
Reactant: CC(C)(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(Oc1ncc(OCc2cc(F)c(C(=O)NS(C)(=O)=O)cc2F)cc1Cl)C(F)(F)F
Temperature: 100 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
To a solution of 4-{[(5-chloro-6-fluoropyridin-3-yl)oxy]methyl}-2,5-difluoro-N-(methylsulfonyl)benzamide (Example 23, 0.092 g, 0.233 mmol) in DMSO (1.0 mL) were added 1,1,1-trifluoro-2-methylpropan-2-ol (0.120 g, 0.937 mmol) and caesium carbonate (0.305 g, 0.936 mmol). The mixture was stirred at 100° C. in a pressure vial for 16 hours. Then 1,1,1-trifluoro-2-methylpropan-2-ol (0.120 g, 0.937 mmol) was added to the mixture and heated at 125° C. for another 24 hours. The reaction mixture was diluted with EtOAc (15.0 mL), washed with water (10.0 mL), aqueous citric solution (10%, 10.0 mL) and water (2×10.0 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was suspended in a mixture of heptane and acetone (8:2, 5.0 mL) and sonicated for 2 minutes. The mixture was filtered to yield the title compound as an off-white solid (0.023 g, 20%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN(C)C=O>[CH2:9]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[N:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(O)cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxy-6-methylpyridine (140 g) was dissolved in dimethylformamide (1.4 L), and with cooling with ice, benzyl chloride (178 ml) was added to it, and stirred overnight at room temperature. The reaction liquid was poured into water with ice, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=40/1 to 2/1) to obtain the entitled compound as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[CH3:9][N:10](C)[CH:11]=O.C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:10]([CH3:11])[CH3:9])[S:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: O=Cc1cc(Br)cs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: O=CO
Product: CN(C)Cc1cc(Br)cs1

Procedure:
A mixture of 4-bromo-2-thiophenecarboxaldehyde (4.8 g), dry dimethylformamide (4.3 ml) and 98% formic acid (1.4 ml), was heated at 120° for 30 h. The cooled mixture was poured into water (100 ml) and basified with anhydrous sodium carbonate. Diethyl ether (2×100 ml) was added and the ethereal solution was extracted with dilute hydrochloric acid (50 ml). The aqueous solution was basified with anhydrous sodium carbonate and extracted with diethyl ether (200 ml). The ethereal extracts were distilled to give the title compound (2.5 g) as a colourless oil, b.p. 70°/0.01 mm.
Reaction SMILES: C(OC/C=C\COC(=O)C)(=O)C.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]([NH:24][C:25]1([C:31]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[NH2:46])[CH2:36][CH:35]2[OH:47])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23].[CH2:48]([N:50](CC)[CH2:51][CH3:52])[CH3:49]>ClCCl.CN(C)C=O>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]([NH:24][C:25]1([C:31]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[NH:46][N:50]3[CH2:51][CH:52]=[CH:49][CH2:48]3)[CH2:36][CH:35]2[OH:47])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]
Reactant: Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Reactant: CCN(CC)CC
Agent: CC(=O)OC/C=C\COC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3NN3CC=CC3)CC2O)CCCCC1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of cis-2-buten-1,4-diol diacetate (1.15 g) in 30 ml of dichloromethane, was added the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-aminophenyl)piperidin-3-ol (1.5 g) obtained in Step 2 of Example 43 in 20 ml of dimethylformamide. 0.44 ml of triethylamine was added to the reaction mixture, which was then stirred overnight at room temperature. 20 ml of ice water was added to the reaction mixture. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 0.7 g of the titled compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][N:6]=[C:5]([SH:8])[N:4]=1.[H-].[Na+].Cl[C:12]1[C:13]([C:18]#[N:19])=[N:14][CH:15]=[CH:16][N:17]=1>CN(C=O)C.C1C=CC=CC=1>[CH3:1][S:2][C:3]1[S:7][N:6]=[C:5]([S:8][C:12]2[C:13]([C:18]#[N:19])=[N:14][CH:15]=[CH:16][N:17]=2)[N:4]=1
Reactant: CSc1nc(S)ns1
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CSc1nc(Sc2nccnc2C#N)ns1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to Example 1 by using 5-(methylthio)-1,2,4-thiadiazole-3-thiol (328 mg, 2.00 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), and 3-chloropyrazine-2-carbonitrile (280 mg, 2.00 mmol) in DMF and benzene (6 ml, 1/1) by stirring at room temperature under nitrogen atmosphere for 2 hr.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:36]=[C:35]([CH3:37])[C:20]([O:21][S:22]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([OH:34])[CH:26]=3)(=[O:24])=[O:23])=[C:19]([CH3:38])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.ClC(Cl)(Cl)C(=N)O[C:43]([CH3:46])([CH3:45])[CH3:44]>CCOC(C)=O.C1CCCCC1>[C:43]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([S:22]([O:21][C:20]2[C:35]([CH3:37])=[CH:36][C:17]([C:9]3[C:10]4[C:14]([CH3:15])=[C:13]([CH3:16])[S:12][C:11]=4[C:2]([Br:1])=[C:3]4[C:8]=3[CH:7]=[CH:6][CH:5]=[CH:4]4)=[CH:18][C:19]=2[CH3:38])(=[O:24])=[O:23])=[CH:26][C:27]=1[OH:34])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)O)c(O)c1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Reaction time: 24 h
Yield: 69 %

Procedure:
At ambient temperature, to a stirred suspension of 4-[4-(9-bromo-2, 3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid (1.033 g, 1.689 mmol) in EtOAc (16.89 mL) was added a solution of t-butyl 2,2,2-trichloroacetimidate (0.7690 g, 3.379 mmol) in cyclohexane (3.379 mL). After 24 h, the reaction was concentrated in vacuo, suspended in CH2Cl2 (10 mL), filtered through a 1"silica gel pad and eluted with 10% acetone/hexane. The filtrate was concentrated to give 0.778 g (69%) of the title compound as an off white solid, mp 168-172° C. 1H NMR (DMSO-d6) δ 1.57 (s, 12 H), 2.15 (s, 6 H), 2.43 (s, 3 H), 7.18 (s, 2 H), 7.45-7.55 (m, 4 H), 7.65 (t, 1 H), 7.96 (d, 1 H), 8.19 (d, 1 H), 10.75 (s, 1 H). IR (KBr) 3400, 2900, 1680, 1380 and 1140 cm-1. mass spectrum (-ESI) m/z 665/667 (M-H). Anal. Calcd. for C33H31BrO6S2 : C, 59.37; H, 4.68; N, 0.00. Found: C, 59.33; H, 4.44; N, 0.10.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.Cl[C:19]1[C:20]([C:25]2([C:31]#[N:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:19]2[C:20]([C:25]3([C:31]#[N:32])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[N:21][CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1
Reactant: N#CC1(c2nccnc2Cl)CCOCC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: N#CC1(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CCOCC1
Temperature: 60 °C

Procedure:
To a solution of 4-(benzo[d]thiazol-2-ylamino)phenol (0.097 g, 0.402 mmol) and 4-(3-chloropyrazin-2-yl)tetrahydro-2H-pyran-4-carbonitrile (0.09 g, 0.402 mmol) in DMSO (1 mL) was added cesium carbonate (0.262 g, 0.805 mmol). The resulting mixture was heated to 60° C. overnight. Purification by Biotage (0-100% EtOAc/hexane) provided product. MS (ESI, pos. ion) m/z: 430.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]>C(OCC)(=O)C.[Pd]>[NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Yield: 98 %

Procedure:
The resulting Boc-Gly-Phe-Gly-OBzl (1.78 g) was dissolved in ethyl acetate (60 ml) and subjected to catalytic reduction for 24 hours in the presence of 5%-Pd-C (1.8 g). The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain Boc-Gly-Phe-Gly-OH (1.41 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].I[CH2:5][C:6]([O:8][CH:9]([C:12]1[CH:28]=[C:27]2[N:15]([CH2:16][C:17]3[C:18]2=[N:19][C:20]2[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14](=[O:29])[C:13]=1[CH3:30])[CH2:10][CH3:11])=[O:7].C(Cl)[Cl:32]>>[ClH:32].[CH3:30][C:13]1[C:14](=[O:29])[N:15]2[C:27](=[CH:28][C:12]=1[CH:9]([O:8][C:6](=[O:7])[CH2:5][N:2]([CH3:3])[CH3:1])[CH2:10][CH3:11])[C:18]1=[N:19][C:20]3[C:25]([CH:26]=[C:17]1[CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: CCC(OC(=O)CI)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Reactant: ClCCl
Reactant: CNC
Product: CCC(OC(=O)CN(C)C)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Product: Cl
Reaction time: 2 h

Procedure:
A stream of dimethylamine was introduced into a solution containing (±)-7-[1-[(iodoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one (50 mg, 0.11 mmol) in anhydrous CH2Cl2 (15 mL). The resulting solution was allowed to stir for 2 h and then was concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and H2O, and the organic layer was washed several times with H2O and dried over sodium sulfate. Into this solution was bubbled a stream of HCl gas, and the resulting cloudy mixture was stirred for 15 min and then was concentrated in vacuo. The residue was dissolved in H2O and lyophilized to afford the title compound as an orange solid. 1H NMR (DMSO-d6) d 8.68 (s, 1H), 8.15 and 8.12 (two overlapping d, 2H), 7.86 (m, 1H), 7.71 (m, 1H), 7.17 (s, 1H), 5.96 (apparent br t, 1H), 5.26 (s, 2H), 4.41 (s, 2H), 2.84 (br s, 6H), 2.26 (s, 3H), 2.20-1.86 (m, 2H), 0.96 (t, J=7.3 Hz, 3H). CIMS (NH3, m/e, rel. int.) 392 (100) [(M+H)+ ]. Anal. Calcd for C23H25N3O3.2HCl.13/8H2O: C, 55.96; H, 6.18; N, 8.51. Found: C, 56.27; H, 6.03; N, 8.04.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:48][O:49][C:50]1[CH:82]=[CH:81][C:53]([CH2:54][N:55]2[C:59]3=[N:60][CH:61]=[CH:62][C:63]([N:64]([CH2:73][CH2:74][N:75]4[CH2:80][CH2:79][O:78][CH2:77][CH2:76]4)[C:65]4[CH:70]=[CH:69][C:68]([NH2:71])=[CH:67][C:66]=4[F:72])=[C:58]3[CH:57]=[N:56]2)=[CH:52][CH:51]=1>CN(C=O)C>[CH3:48][O:49][C:50]1[CH:51]=[CH:52][C:53]([CH2:54][N:55]2[C:59]3=[N:60][CH:61]=[CH:62][C:63]([N:64]([CH2:73][CH2:74][N:75]4[CH2:80][CH2:79][O:78][CH2:77][CH2:76]4)[C:65]4[CH:70]=[CH:69][C:68]([NH:71][C:15]([C:12]5[C:13](=[O:14])[N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[N:9]=[CH:10][CH:11]=5)=[O:17])=[CH:67][C:66]=4[F:72])=[C:58]3[CH:57]=[N:56]2)=[CH:81][CH:82]=1
Reactant: COc1ccc(Cn2ncc3c(N(CCN4CCOCC4)c4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2ncc3c(N(CCN4CCOCC4)c4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Reaction time: 0.25 h
Yield: 51.4 %

Procedure:
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (0.0310 g, 0.132 mmol) (prepared according to the procedure of Example 19, Step C) was taken up in DMF (1 mL). EDCI (0.0422 g, 0.220 mmol), HOBt (0.0298 g, 0.220 mmol), and DIEA (0.0384 ml, 0.220 mmol) were then added. After stirring under N2 for 15 minutes, N1-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-fluoro-N1-(2-morpholinoethyl)benzene-1,4-diamine (0.021 g, 0.0441 mmol) was added in DMF (1 mL). After stirring for 5.5 hours, DCM was removed. The product was taken up into EtOAc and washed with diluted NaHCO3 and brine. The product was dried over Na2SO4, filtered and concentrated. Purification via Flash Si 5 g eluting with 1-5% MeOH/DCM with NH4OH to obtain 15.7 mg (51%) of product as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 11.88 (s, 1H), 8.41 (d, 1H), 8.24 (m, 2H), 7.93 (dd, 1H), 7.63 (m, 2H), 7.43 (m, 1H), 7.35 (m, 1H), 7.27 (m, 4H), 6.80 (m, 2H), 6.61 (br s, 1H), 6.31 (d, 1H), 5.48 (s, 2H), 3.94 (t, 2H), 3.75 (s, 3H), 3.65 (t, 3H), 2.88 (s, 1H), 2.75 (t, 2H), 2.47 (t, 4H); 19F NMR (376 MHz, CDCl3) −111.41 (s, 1F), −117.59 (s, 1F); LRMS (apci pos): 693.3 (M+H)+.