Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]1[N:17]=[C:16]([CH2:18][CH2:19][C:20]2([CH3:28])[O:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][O:21]2)[N:15]=[C:14]2[C:10]=1[N:11]=[C:12](Br)[N:13]2[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:44]1[CH:48]=[CH:47][N:46]=[N:45]1>CN(C=O)C>[CH2:1]([N:8]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]1[N:17]=[C:16]([CH2:18][CH2:19][C:20]2([CH3:28])[O:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][O:21]2)[N:15]=[C:14]2[C:10]=1[N:11]=[C:12]([N:45]1[N:46]=[CH:47][CH:48]=[N:44]1)[N:13]2[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(Br)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(CCC3(C)OCC(C)(C)CO3)nc21
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(-n2nccn2)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(CCC3(C)OCC(C)(C)CO3)nc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of dibenzyl-{8-bromo-9-methyl-2-[2-(2,5,5-trimethyl-[1,3]dioxan-2-yl)-ethyl]-9H-purin-6-yl}amine (1.9 g, 3.50 mmol) in anhydrous DMF (20 ml) were added K2CO3 (0.72 g, 5.2 mmol) followed by 1H-1,2,3-triazole (362 mg, 5.2 mmol). The mixture was stirred overnight at 100° C. The solvent was evaporated under reduced pressure to give a residue that was purified by flash chromatography (DCM/MeOH: 93/7).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([C:17]3[CH2:22][CH2:21][N:20](C(OCC4C=CC=CC=4)=O)[CH2:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[N:9]=[C:8]([C:33]([F:36])([F:35])[F:34])[CH:7]=1.[H][H]>CO.[Pd]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:14]=[CH:15][CH:16]=2)[N:9]=[C:8]([C:33]([F:34])([F:35])[F:36])[CH:7]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CC=C(c2cccc(-n3nc(C(F)(F)F)cc3-c3ccco3)c2)CC1
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)c1cc(-c2ccco2)n(-c2cccc(C3CCNCC3)c2)n1
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a stirred solution of 64 (430 mg, 0.871 mmol) in MeOH (4.4 mL) was added palladium on carbon (9.27 mg, 0.087 mmol). Under a balloon of hydrogen the suspension was allowed to stir for 2 h. It was then filtered and filtrate evaporated. The crude was used without any further purification. The title product 65 (315 mg, 100% yield) was isolated as a colorless oil. LRMS (ESI): calc. 361.4; found 362.5 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[CH3:24]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Reactant: CB1OB(C)OB(C)O1
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: C1COCCO1
Product: COC(=O)c1nc(C)c2cc(Sc3ccccc3)ccc2c1O
Yield: 28.2 %

Procedure:
1-Bromo-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid methyl ester (0.2 g), tetrakis(triphenylphosphine)palladium (60 mg), trimethyl boroxine (65 mg), and potassium carbonate in 1,4-dioxane (4 ml) were heated in a microwave reactor (sealed tube) for 10 min at 140° C. After cooling reaction mixture was concentrated and partitioned between 1 N hydrochloric acid and ethyl acetate. Organic layer dried over magnesium sulfate and filtered. Filtrate concentrated and separated by silica gel chromatography (eluting with 2% ethyl acetate in methylene chloride) to give the title compound (47 mg). MS-(+)-ion M+1=326.1.
Reaction SMILES: C12OC3CC([O:9]1)C(C=C3)C2.C(=O)(O)[O-].[K+].[C:16](#[N:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.OO>CO.C(Cl)Cl>[C:16]([NH2:23])(=[O:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ccccc1
Reactant: C1=CC2CC3OC1CC2O3
Agent: O=C([O-])O
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1ccccc1
Reaction time: 10 h

Procedure:
To a solution of 165 mg of racemic 9,10-dioxatricyclo[4,3,1,03,8 ]dec-4-ene in 4 ml of methanol are added, with stirring and at room temperture 865 mg of potassium bicarbonate and 750 mg of benzonitrile. To this mixture are added at intervals of 8 hours 5 positions each of 0.3 ml of 30% hydrogen peroxide and stirring is continued for 10 hours. methylene chloride (25 ml) is then added to the reaction mixture, which is washed with 2% sodium hydrogen carbonate solution, dried over sodium sulphate and concentrated, Benzamide which has formed is removed by crystallisation from methylene chloride/pentane. The residual oil can be used directly in the next reaction, or chromatographed on 22 g of basic aluminium oxide (activity level IV). Elution with petroleum ether/benzene (7:3) yields the racemic mixture of 4β, 5β-epoxy-9,10-dioxatricyclo[4,3,1,03,8 ]decane of the formula ##SPC18##
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([N:13]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[C:25]1([S:22]([N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:31])=[O:5])=[CH:8][CH:9]=2)(=[O:24])=[O:23])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N(Cc2ccc(Cl)cc2)S(=O)(=O)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(N(Cc2ccc(Cl)cc2)S(=O)(=O)c2ccccc2)cc1
Yield: 62.2 %

Procedure:
A solution of 4-[benzenesulfonyl-(4-chloro-benzyl)-amino]-benzoic acid tert-butyl ester (2.1 g, 4.4 mmol) in 10% trifluoroacetic acid/dichloromethane (50 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between sodium hydrogen carbonate (saturated solution, 25 mL) and dichloromethane (20 mL). The aqueous layer was separated, acidified (pH 1) using 10% HCl (aq) and the resulting solution extracted with dichloromethane (3×75 mL). The organics were combined, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a white solid (1.1 g, 62% yield)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[N:10]([CH3:23])[C:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1.[C:29]([Cu])#[N:30].[C-]#N.[Na+]>CN(C=O)C>[C:29]([C:2]1[CH:3]=[C:4]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[N:10]([CH3:23])[C:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)#[N:30]
Reactant: N#C[Cu]
Reactant: Cc1ccc(C(=O)c2ccc(Cc3ccc(NS(C)(=O)=O)cc3Br)n2C)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2ccc(Cc3ccc(NS(C)(=O)=O)cc3C#N)n2C)cc1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
N-{3-Bromo-4-[5-(4-methylbenzoyl)-1-methyl-1H-pyrrol-2-ylmethyl]phenyl}methane-sulfonamide (320 mg, 0.69 mmol) was dissolved in DMF. CuCN (120 mg, 1.38 mmol) was added and the suspension was refluxed for 4 h. The mixture was cooled to room temperature, and NaCN (2.0 g in 10 ml of water) was added. After 0.5 h the mixture was extracted with ethyl acetate and the extracts were washed with water, and brine, and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by preparatory TLC (hexane-ethyl acetate) to give N-{3-cyano-4-[5-(4-methylbenzoyl)-1-methyl-1H-pyrrol-2-yl-methyl]phenyl}methanesulfonamide (190 mg, 67%) as a solid, mp 171-172° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:23]1[CH2:27][C@@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1.Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:23]1[CH2:27][C@@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(Br)c1
Reactant: O[C@@H]1CNC[C@@H]1O
Agent: Cl
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@@H](O)[C@@H](O)C2)c(Br)c1

Procedure:
A solution of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 500 mg, 1.32 mmol), (3S,4R)-pyrrolidine-3,4-diol (170 mg, 1.65 mmol) and TEA (369 μL, 2.64 mmol) in DMSO (1322 μL) was stirred at 90° C. for 20 h. The RM was treated with 0.5 M HCl (15 mL) and extracted with EtOAc (30 mL). The aq. phase was back-extracted with EtOAc (2×20 mL) and the combined organic layers were washed with sat. NaHCO3 and brine, and dried over Na2SO4. The crude product was purified by flash chromatography (RediSep® Silica gel column, 40 g, cyclohexane/EtOAc, from 50% to 100% EtOAc) to yield the title compound as a white amorphous solid. UPLC-MS (Condition 3) tR=1.02 min, m/z=461.2-463.1 [M+H]+, m/z=459.1-461.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.40 (dd, J=9.90, 4.52 Hz, 2H) 3.67 (dd, J=9.66, 5.26 Hz, 2H) 4.06-4.16 (m, 2H) 4.94 (d, J=4.65 Hz, 2H) 6.86 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.80-7.91 (m, 3H) 8.13 (d, J=2.20 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:29])[N:7]([CH2:19][C@@H:20]([OH:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[N:22]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)([CH3:4])[CH3:3].[Sn](Cl)Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CO>[CH3:4][C:2]([O:5][C:6](=[O:29])[N:7]([CH2:19][C@@H:20]([OH:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[N:22]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc([N+](=O)[O-])cc1)C[C@@H](O)c1cccc(Cl)n1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCc1ccc(N)cc1)C[C@@H](O)c1cccc(Cl)n1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
To a solution of 1.00 g (2.37 mmol) of (R)-N-[2-(4-nitrophenyl)ethyl]-2-hydroxy-2-(6-chloro-2-pyridyl)ethylcarbamic acid 1,1-dimethylethyl ester in 60 mL of methanol under an atmosphere of nitrogen was added 1.35 g (7.12 mmol) of tin(II) chloride. The mixture was heated at reflux for 5 h then cooled to room temperature. Saturated aqueous sodium bicarbonate solution was added followed by ethyl acetate. The resulting emulsion was filtered through Celite and the organic phase separated. The aqueous phase was re-extracted twice with ethyl acetate. The combined organic phase was washed twice with water, brine, dried over magnesium sulfate and the solvent removed in vacuo. Biotage chromatography (40M column, 30, 35% ethyl acetate-hexanes) afforded 510 mg (55%) of (R)-N-[2-(4-aninophenyl)ethyl]-2-hydroxy-2-(6-chloro-2-pyridyl)ethylcarbamic acid 1,1-dimethylethyl ester.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][N:12]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][N:14]=[C:13]1[CH3:20])(=O)=O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[N:1]([CH2:10][CH2:11][N:12]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][N:14]=[C:13]1[CH3:20])=[N+:2]=[N-:3]
Reactant: Cc1ncc([N+](=O)[O-])n1CCOS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncc([N+](=O)[O-])n1CCN=[N+]=[N-]

Procedure:
To 10 parts of sodium azide is added a solution of 32 parts of 2-(5-nitro-2-methyl-1-imidazolyl)ethyl methanesulfonate (Ger. Pat. No. 2,030,314) in 250 parts of warm N,N-dimethylformamide. The resultant mixture is stirred at approximately 50° for 6 hours, then diluted with 1000 parts of cold water. Sufficient potassium carbonate is added to insure basicity. The mixture thus obtained is extracted with toluene. The toluene extract is washed with water, dried over anhydrous potassium carbonate, and stripped of solvent by vacuum distillation, affording 1-(2-azidoethyl)-2-methyl-5-nitroimidazole as a yellow oil which is further purified by crystallization from ether. Isolated by filtration, washed with a 1:1 mixture of ether and hexane, and dried in air the purified product melts at 53°-54°. It has the formula ##SPC6##
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[NH:9]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:9]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)CCCCl
Reactant: Oc1ccc(Nc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCOc1ccc(Nc2ccccc2)cc1
Reaction time: 4 h

Procedure:
A mixture of 198 g. of methyl 4-chlorobutyrate, 269 g. of p-anilinophenol, and 636 g. of anhydrous potassium carbonate, all in 500 ml. of N,N-dimethylformamide was heated at 140° C. while stirring for 4 hours and about 300 ml. of the N,N-dimethylformamide was removed by distillation. The residue was poured into ice water and the resulting mixture was extracted with benzene. The dried benzene extract was chromatographed through a column of neutral alumina and the benzene solvent was stripped from the eluent leaving the product, methyl 4-(p-anilinophenoxy)butyrate, as a dark amber liquid. This ester was sufficiently pure to be used as an antioxidant. Crystallization of the crude ester from ethanol afforded a solid, mp. 40°-41° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][C:21]4[N:26](CCC#N)[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O=C1COC2N=[C:48](C3C=CC(C4(NC(=O)OC(C)(C)C)CCC4)=CC=3)[C:49](C3C=CC=CC=3)=[CH:50][C:43]=2[NH:42]1.BrCCCC#N>>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:20][C:21]4[N:26]([CH2:48][CH2:49][CH2:50][C:43]#[N:42])[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCC#N)C(=O)CO4)cc2)CCC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: N#CCCCBr
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCCC#N)C(=O)CO4)cc2)CCC1

Procedure:
Following the procedure for tert-butyl(1-(4-(1-(2-cyanoethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate, tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.212 mmol) was reacted with 4-bromobutanenitrile (94 mg, 0.636 mmol) to afford the title compound (68 mg. 1H NMR (500 MHz, CDCl3): 7.20-7.32 (10H, m), 5.1 (1H, br), 4.90 (2H, s), 4.11 (2H, m), 2.44-2.50 (6H, m), 2.05-2.13 (3H, m), 1.79-1.84 (1H, m), 1.27-1.36 (9H, br).
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15]N(C=O)C.CI>O>[CH3:15][O:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2c1oc1ccccc12
Reactant: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cccc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of 4-hydroxydibenzo[b,d]furan (2 g, 0.0109 mol) in DMF (5 mL) potassium carbonate (3.2 g, 0.0232 mol) and methyl iodide (1.35 mL, 0.0217 mol) was added. The reaction slurry was stirred at room temperature for 3 h. Subsequently the reaction mixture was poured into the cold water (100 mL) and extracted with hexane (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated at reduced pressure to, give the desired product in 66% yield, Rf 0.74 (Ethyl acetate:Hexane (3:7); MS m/z: 199.1 (M+1).
Reaction SMILES: C[Al](C)C.CCCCCC.[CH3:11][S:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1.[Cl:20][C:21]1[C:22]([N:27]2[C:31]3=[N:32][CH:33]=[N:34][C:35]([O:36][C@@H:37]([CH2:42][O:43][CH2:44][CH3:45])[C:38](OC)=[O:39])=[C:30]3[CH:29]=[N:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1>C1(C)C=CC=CC=1>[Cl:20][C:21]1[C:22]([N:27]2[C:31]3=[N:32][CH:33]=[N:34][C:35]([O:36][C@@H:37]([CH2:42][O:43][CH2:44][CH3:45])[C:38]([NH:19][C:16]4[CH:15]=[CH:14][C:13]([S:12][CH3:11])=[CH:18][N:17]=4)=[O:39])=[C:30]3[CH:29]=[N:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: CSc1ccc(N)nc1
Reactant: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)OC
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(SC)cn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2M Trimethylaluminium in hexane (0.457 mL, 0.91 mmol) was added to 5-(methylthio)pyridin-2-amine (CAS no. 77618-99-6) (0.111 g, 0.79 mmol) in toluene (22 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-ethoxypropanoate (Intermediate L2) (0.300 g, 0.79 mmol) in toluene (6 mL) was added dropwise at this temperature. After the addition was complete, the solution was allowed to warm to ambient temperature and was then heated at reflux for 16 hours. The mixture was allowed to cool to ambient temperature and left standing for 2 days. The reaction mixture was concentrated, diluted with ethyl acetate (100 mL) then washed with saturated brine (50 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 0 to 3% MeOH in DCM to afford the product.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([N:19]([CH3:37])[CH:20]4[CH2:36][CH2:35][C:23]5([CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[CH:16]=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1.Cl.CCOC(C)=O>C(Cl)Cl>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([N:19]([CH3:37])[CH:20]4[CH2:36][CH2:35][C:23]5([CH2:27][NH:26][CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[CH:16]=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cc1c2ccc(Nc3nccc(N(C)C4CCC5(CC4)CCN(C(=O)OC(C)(C)C)C5)n3)cc2nn1C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c2ccc(Nc3nccc(N(C)C4CCC5(CCNC5)CC4)n3)cc2nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of tert-butyl 8-((2-((2,3-dimethyl-2H-indazol-6-yl)amino)pyrimidin-4-yl)(methyl)amino)-2-azaspiro[4.5]decane-2-carboxylate (657 mg, 1.3 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 40 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (250 mL×3). The combined organic phases were washed with brine (250 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/5) to give the title compound as a beige solid (0.30 g, 56.9%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:11][C:4]=2[CH:3]=1.C(Cl)(Cl)Cl.O.[NH2:23][NH2:24]>>[NH:23]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:11][C:4]=2[CH:3]=1)[NH2:24]
Reactant: C=CCCC(=O)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCCC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
12.3 g of 3-chloro-5,6,7,8-tetrahydro-6-(4-pentenoyl)pyrido[4,3-c]pyridazine are stirred in 40 cc of hydrazine hydrate at a bath temperature of 90° for 3 hours. The mixture is cooled with ice, 100 cc of chloroform are added, and the excess hydrazine is separated. Upon concentrating the chloroform phase, the crude title compound is obtained as an oil. This is converted to bis[3-hydrazino-5,6,7,8-tetrahydro-6-(4-pentenoyl)pyrido[4,3-c]pyridazine]trisfurmarate by boiling with 4 g of fumaric acid in 50 cc of absolute ethanol. M.P. 132°-134° (decomp., from absolute ethanol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([F:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.[Br:12]N1C(=O)CCC1=O.BrBr>O>[Br:12][CH:10]([C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([Cl:8])[C:5]=1[F:9])[CH3:11]
Reactant: CCc1nc(Cl)nc(Cl)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: BrBr
Solvent: O
Product: CC(Br)c1nc(Cl)nc(Cl)c1F
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of the compound of part (i) (400 g), N-bromosuccinimide (730 g), azoisobutyronitrile (33.7 g), bromine (65.5 g) and water (6.4 L) was heated at 80–85° C. for 5 hours. Further N-bromosuccinimide (183 g) was added, heating continued for 2 hours then further azoisobutyronitrile (33.7 g) added. After heating for 2 hours at 85° C. further azoisobutyronitrile (33.7 g) was added and heating continued for 3 hours. The reaction was cooled, diluted with water (4 L) and extracted with dichloromethane (2×3 L). The combined organic extracts were washed with a solution of sodium metabisulphate (600 g) in water (2.5 L), followed by water (3 L). The solvent was removed by evaporation under reduced pressure, toluene (1.0 L) added and the solution concentrated under reduced pressure to give the product as an oil (534 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19](O)=[O:20])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH3:29][NH2:30]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[CH:18]=[C:17]([C:19]([NH:30][CH3:29])=[O:20])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CN
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Agent: Cl
Product: CNC(=O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to methylamine HCl via General Procedure B. The product was purified via reverse phase HPLC to give 36.4 mg of 131. MS (Q1) 395.2 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:8][CH:9]=1)=[O:4].C(N(CC)CC)C.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:33]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[S:38]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)(=[O:40])=[O:39])=[CH:8][CH:9]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COC(=O)c1ccc(CCCNCCCc2cccc(Cl)c2)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCCN(CCCc2cccc(Cl)c2)S(=O)(=O)c2cccnc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(3-(3-(3-chloro-phenyl)-propylamino)-propyl)-thiophene-2-carboxylic acid methyl ester (from Preparation 8, 0.0855 g, 0.243 mmol), triethylamine (0.0541 g 0.534 mmol), and pyridine-3-sulfonyl chloride hydrochloride (from Preparation 2, 0.0572 g, 0.267 mmol) in 10 mL CH2Cl2 combined at 0° C. was stirred at room temperature overnight. The organic solution was washed with water, saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound of Step A as an oil. MS 494 (M+1).