Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH3:21])=C([CH:18]=1)C(O)=O)(=[O:9])[CH3:8]>ClCCl.CN(C)C=O>[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH3:21])=[C:1]([CH:18]=1)[C:2]([Cl:4])=[O:3])(=[O:9])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOc1ccc(C(C)=O)cc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccc(C(C)=O)cc1C(=O)Cl

Procedure:
Oxalyl chloride (3.66 g, 0.029 mol) was added dropwise to a stirred solution of 5-acetyl-2-ethoxybenzoic acid (3.0 g, 0.014 mol) in dichloromethane (15 ml) and dimethylformamide (0.1 ml) After 3 hours at room temperature, the solvent was removed by evaporation under vacuum and the residue axeotroped with hexane (3×30 ml) to give the title compound, which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:5]([F:15])=[C:6]([Cl:14])[C:7]([F:13])=[C:8]([CH:12]=1)[C:9](O)=[O:10])([O-:3])=[O:2].C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C=O)C>[N+:1]([C:4]1[C:5]([F:15])=[C:6]([Cl:14])[C:7]([F:13])=[C:8]([CH:12]=1)[C:9]([Cl:19])=[O:10])([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(Cl)c1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc([N+](=O)[O-])c(F)c(Cl)c1F
Reaction time: 14 h

Procedure:
An amount of 3.47 g (0.015 mole) of 5-nitro-3-chloro-2,4-difluorobenzoic acid and 2.03 g (0.016 mole) of oxalyl chloride are dissolved in 15 ml of dichloromethane then two drops of DMF are added. The reaction is stirred for 14 hours then the solvent is evaporated under vacuum to afford the desired product.
Reaction SMILES: FC1C=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4]C=1.[NH2:38][C:39]1[N:44]=CC(B2OC(C)(C)C(C)(C)O2)=C[N:40]=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:4]=[N:38][C:39]([NH2:44])=[N:40][CH:6]=4)[CH2:15][CH2:16]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:34])([F:35])[F:33]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2cnc(N)nc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using (2-aminopyrimidin-5-yl)boronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=514, obsd.=514).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]([N+:20]([O-])=O)=[CH:15][C:16]=32)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26](N)[CH2:27][CH2:28][CH3:29]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]([NH:20][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][C:16]=32)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC(C1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc12
Reactant: CCCCN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCNc1cc2c(cc1[N+](=O)[O-])C1CC2CN(C(=O)OC(C)(C)C)C1
Reaction time: 4 h

Procedure:
4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (500 mg, 1.43 mmol) and 1-butylamine (1.42 mL, 14.3 mmol) were combined in THF (5 mL) and stirred 4 hours. The mixture was diluted with EtOAc (50 mL) and washed with H2O (3×30 mL) then dried (Na2SO4), filtered and concentrated to an oil. This oil was passed through a Silica gel filter column to remove baseline impurities eluting with 30% EtOAc/hexanes (510 mg, 1.41 mmol, 99%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2O)cc1
Product: COc1ccc(CC(=O)c2ccc(OCc3ccccc3)cc2O)cc1
Yield: 94.7 %

Procedure:
Using the previous procedure and starting from 1-(2,4-dihydroxyphenyl)-2-(4-methoxyphenyl)ethanone (8.0 g, 31.0 mmol) and benzyl alcohol (3.37 mL, 32.55 mmol), 10.23 g (95%) of the title compound was obtained as a white solid: mp 97-98° C. (lit. 93-95° C.); IR (KBr) 1635, 1611, 1512, 1496, 1387, 1351, 1289, 1227, 1173, 1131, 1029, 994, 948, 842, 830, 791, 745, 725, 695, 535 cm−1; 1H NMR (250 MHz, CDCl3) δ 12.73 (s, 1H), 7.75 (d, J=9.6 Hz, 1H), 7.33-7.40 (m, 5H), 7.18 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 6.53-6.49 (m, 2H), 5.07 (s, 2H), 4.14 (s, 2H), 3.78 (s, 3H); 13C NMR (69.3 MHz, CDCl3) δ 202.77, 166.19, 165.63, 159.10, 136.26, 132.51, 130.82, 129.15, 128.77, 127.97, 126.71, 114.63, 113.73, 108.71, 102.48, 70.6.5, 55.69, 44.38; HRMS calculated for C22H20NaO4 (M+Na)+ 371.1259; found 371.1265.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH2:20]([N:27]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCC.CCOCC>[CH2:20]([N:27]1[CH2:31][CH2:30][C:29]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:8])=[O:7])([OH:32])[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CC(C)(C)NS(=O)(=O)c1ccccc1C1(O)CCN(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39.5 %

Procedure:
To a solution of N-(tert-butyl)benzenesulfonamide (536 mg, 0.00251 mol) in ether (10 mL, 0.1 mol) was added 1.7 M of tert-butyllithium in pentane (4.4 mL) under nitrogen at −78° C. The mixture was stirred at −78 Celsius for 15 min, then at 0 Celsius for 1 hour, and then cooled down to −78 Celsius again. A solution of 1-benzylpyrrolidin-3-one (400.0 mg, 0.002283 mol) in ether (3 mL) was added to the above solution. The reaction solution was stirred at ±78 Celsius for 2 hours, then quenched with saturated NH4Cl aqueous solution, and then extracted with EtOAc. The organic phase was washed with brine, then dried over MgSO4. The residue was purified by flash chromatography on silica gel column with 30% AcOEt in hexanes to give the desired compound (350 mg, 39% yield). MS (ESI): 389.1 (M+
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1

Procedure:
Phenol is reacted with p-chlorobenzoyl chloride in a Friedel-Crafts reaction in the presence of aluminium chloride to give 4-chloro-4'-hydroxybenzophenone, m.p. 179°-181° C. (A). To a solution of this (5 g.) in pyridine (6 ml.) was added methanesulphonyl chloride (2.5 g.), at room temperature. The reactants were heated on a steam bath for 11/2 hours and the liquid reaction product poured into dilute hydrochloric acid to give a solid which was filtered and air-dried. This solid was recrystallised from industrial methylated spirits to give 4-chloro-4'-methylsulphonyloxybenzophenone, m.p. 120°-121° C. (B). To a solution of this (9.35 g.) in ethanol (200 ml.) was addedd hydrazine hydrate (8 ml.) followed by glacial acetic acid (1.5 ml.). The mixture was heated under reflux with stirring for 17 hours. The solvent was evaporated under reduced pressure to give an oil which was extracted with chloroform. The extract was washed with water, aqueous sodium hydroxide and water and then dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give an oil. On standing this crystallised to give 4-chloro-4'-methylsulphonyloxybenzophenone hydrazone, m.p. 70°-110° C. (C). This product (5 g.) was heated under reflux with acetone (25 ml.) for 24 hours. The mixture was then evaporated under reduced pressure to give 4-chloro-4'-methylsulphonyloxybenzophenone isopropylidenehydrazone m.p. 148°-9° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:21]=[C:20]([CH2:22][C:23]([OH:25])=[O:24])[NH:19][N:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:26][CH3:27].[OH:28][CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.Cl>CC(N(C)C)=O>[OH:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([NH:16][C:17]4[CH:21]=[C:20]([CH2:22][C:23]([OH:25])=[O:24])[NH:19][N:18]=4)=[N:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[O:26][CH3:27])[CH2:32][CH2:31]1
Reactant: OCC1CCNCC1
Reactant: COc1cc2c(Nc3cc(CC(=O)O)[nH]n3)ncnc2cc1OCCCCl
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3cc(CC(=O)O)[nH]n3)ncnc2cc1OCCCN1CCC(CO)CC1
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetic acid (7.83 g, 20 mmol) in dimethylacetamide (30 ml) was reacted with 4-(hydroxymethyl)piperidine (8.05 g, 70 mmol) at 100° C. for 2 hours. The solvent was evaporated, and the residue triturated with a mixture of dichloromethane:ethyl acetate (1:1). The paste was recovered, and dissolved in a mixture of dichloromethane:methanol. Ethanolic HCl (7.0 N) (10 ml, 70 mmol) was added to the mixture and the solvents were evaporated. Methanol (200 ml) was added to the solid and the mixture was stirred for 0.5 hour. The reaction mixture was reduced in volume and dichloromethane added. The resultant solid was recovered by filtration and dried to yield {3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic acid (6.5 g, 60% yield) as a yellow solid:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:20])[S:13]([CH2:16][CH2:17][CH2:18][Cl:19])(=[O:15])=[O:14])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH:37]=[N:38][NH:39]3)O1>>[NH:39]1[C:40]2[C:36](=[C:35]([C:2]3[N:3]=[C:4]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[C:5]4[S:10][C:9]([CH2:11][N:12]([CH3:20])[S:13]([CH2:16][CH2:17][CH2:18][Cl:19])(=[O:15])=[O:14])=[CH:8][C:6]=4[N:7]=3)[CH:43]=[CH:42][CH:41]=2)[CH:37]=[N:38]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)S(=O)(=O)CCCCl
Product: CN(Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)S(=O)(=O)CCCCl

Procedure:
3-Chloro-propane-1-sulfonic acid (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamide was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification on silica yielded 3-chloro-propane-1-sulfonic acid [2-(1H-indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-methyl-amide.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:8][S:9]([CH2:12][C@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:31]([N:8]([CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[S:9]([CH2:12][C@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])(=[O:10])=[O:11])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H](C)CS(=O)(=O)NC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)CS(=O)(=O)N(Cc1ccccc1)C(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar and N2 inlet was charged with 1.11 g of methyl 3-[N-(diphenylmethyl) aminosulfonyl]-2(R)-methylpropionate, 447 mg K2CO3, 347 mL benzyl bromide in 20 mL DMF. The reaction was stirred overnight, concentrated in vacuo and partioned between ethyl acetate and water. The organic phase was washed with brine, dried and concentrated in vacuo to 1.2 g of a clear oil. Flash chromatography on silica gel (30% ethyl acetate/hexanes) afforded 730 mg of methyl 3-[N-(benzyl)-N-(diphenylmethyl)aminosulfonyl]-2(R)-methylpropionate. HRMS (M+Li): calcd. 444.1821, obs 444.1865.
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1.Cl[CH2:14][CH2:15][CH2:16][C:17]#[N:18]>C(OCC)C.C1(C)C=CC=CC=1>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:17]2[CH2:16][CH2:15][CH2:14][N:18]=2)=[CH:7][CH:6]=1
Reactant: N#CCCCCl
Reactant: ClCc1ccc(Cl)cc1
Agent: II
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Clc1ccc(CC2=NCCC2)cc1
Reaction time: 0.75 h

Procedure:
Magnesium turnings (4.04 g, 168 mmol) are introduced into diethyl ether abs. (10 ml), and the formation of the Grignard reagent is started with a crystal of iodine and 4-chlorobenzyl chloride (2.2 ml, 2.7 g, 16.8 mmol). The remaining amount of 4-chlorobenzyl chloride (19 ml, 24 g, 148.7 mmol), dissolved in diethyl ether abs. (150 ml), is added dropwise (45 min) such that the mixture boils vigorously. After addition is complete, the mixture is refluxed by heating for a further 1.5 h. A solution of 4-chlorobutyronitrile (16.6 g, 160 mmol) in diethyl ether abs. (150 ml) is added dropwise to the solution of the 4-chlorobenzyl Grignard reagent prepared in this way (45 min), the mixture is stirred for a further 45 min after the addition, toluene abs. (200 ml) is added and diethyl ether is distilled off over a bridge until a temperature of 95° C. is reached in the bottom (2.5 h). The mixture is cooled in an ice bath and dil. HCl (10%) is added at 25-30° C. until a pH of 2-3 is reached in the depositing aqueous phase. The toluene/ether phase is separated and extracted 3 times with HCl (10%, 150 ml). The collected HCl phase is washed again with toluene (100 ml) and then rendered alkaline (pH 9-10) with NaOH (32%). The depositing oily pyrroline phase is taken up in diethyl ether (300 ml), dried over K2CO3 and concentrated. The concentrated ether phase (to 50%-55% product content) is used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([CH3:19])=[CH:4][N:3]=1.[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21].Cl>O1CCOCC1.C(O)(C)C>[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH:33][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=4[C:11]([NH:13][CH3:14])=[O:12])[C:5]([CH3:19])=[CH:4][N:3]=3)[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CCN1CCc2ccc(Nc3ncc(C)c(Nc4ccccc4C(=O)NC)n3)cc2CC1
Yield: 38.7 %

Procedure:
2-(2-Chloro-5-methyl-pyrimidin-4-ylamino)-N-methyl-benzamide (32 mg, 0.12 mmol) and 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (24 mg, 0.13 mmol) were combined with 1 drop of a solution of 4N hydrochloric acid in dioxane and 2 mL isopropanol and subjected to microwave irradiation (CEP) at 170° C. for 150 minutes. The reaction mixture was concentrated and the organics were partitioned between dichloromethane and saturated sodium bicarbonate solution (100 mL each). The dichloromethane extract was separated, dried (sodium sulfate), and concentrated to afford a material which was purified on silica gel (methanol:dichloromethane gradient elution) to afford 20 mg (39%) of a white foam -2-[2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-5-methyl-pyrimidin-4-ylamino]-N-methyl-benzamide. MS: 431.20 (M+H); 1H NMR (d6-dmso): δ 11.20 (s, 1H), δ 8.99 (s, 1H), δ 8.86 (d, J=8 Hz, 1H), δ 8.74 (d, J=4 Hz, 1H), δ 7.97 (s, 1H), δ 7.75 (d, J=8 Hz, 1H), δ 7.49 (s, 1H), δ 7.45 (t, J=8 Hz, 1H), δ 7.38 (d, J=8 Hz, 1H), δ 7.08 (t, J=8 Hz, 1H), δ 6.97 (d, J=8 Hz, 1H), δ 2.82 (d, J=6 Hz, 3H), δ 2.80 (m, 2H), δ 2.70-2.40 (m, 8H), δ 2.10 (s, 3H), δ 1.01 (t, J=8 Hz, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:33]([N:35](CC)[CH2:36][CH3:37])[CH3:34].N1CCCC1>C(#N)C>[CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][N:35]3[CH2:36][CH2:37][CH2:34][CH2:33]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(C#CCCCCCl)c2n1
Reactant: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCNC1
Product: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(C#CCCCCN3CCCC3)c2n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 117.8 %

Procedure:
To a solution of 5-butyl-3-(6-chlorohex-1-yn-1-yl)-N-(3,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (3.334 g, 7.31 mmol) in anhydrous acetonitrile (4 mL) was added triethylamine (3.06 mL, 21.94 mmol) and pyrrolidine (1.831 mL, 21.94 mmol). The solution was stirred at 70° C. for 18 hours. A further equivalent of pyrrolidine (0.61 mL, 7.31 mmol) and triethylamine (1.019 mL, 7.31 mmol) were added to the reaction mixture. The solution was stirred at 70° C. for a further 3 hours. The cooled reaction mixture was evaporated in-vacuo and the residue partitioned between ethyl acetate and water/brine (1:1). The organic phase was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield a sticky brown gum (4.226 g). The gum was dissolved in the minimum volume of dichloromethane, loaded onto a 340 g silica pre-conditioned cartridge and purified by chromatography using dichloromethane over 1 column volume followed by 0-30% methanol (+1% triethylamine) in dichloromethane gradient over 14 column volumes followed by 30% methanol (+1% triethylamine) in dichloromethane over 3 column volumes. Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a sticky brown gum (1.838 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.[Cl:11]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.CCCCCCC>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[Cl:11]
Reactant: COc1cc(Cl)cc(Br)c1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(Cl)c(Br)c1
Yield: 197.3 %

Procedure:
1-Bromo-3-chloro-5-methoxybenzene (Preparation 22, 6.0 g, 27 mmol) and trichloroisocyanuric acid (2.3 g, 9.9 mmol) were stirred in dimethylformamide (100 ml) at 50° C. for 3 hours. N-Heptane was added and the mixture filtered to remove insoluble impurities. The mixture was then concentrated in vacuo and the residue purified by silica gel column chromatography, eluting with 90:10 heptane:ethyl acetate to afford the title compound as a white solid (5.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=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>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: COc1ccccc1B(O)O
Reactant: Nc1cnc(Br)cn1
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: CN(C)C=O
Product: COc1ccccc1-c1cnc(N)cn1
Temperature: 110 °C
Yield: 15.6 %

Procedure:
A solution of 2-amino-5-bromopyrazine (1.16 g, 6.67 mmol) and 2-methoxyphenylboronic acid (1.17 g, 7.70 mmol) in N,N-dimethylformamide (15 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (193 mg, 0.17 mmol) and potassium carbonate (1.87 g, 13.34 mmol). The mixture was heated at 110° C. overnight. The reaction mixture was extracted with chloroform and water. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 ethyl acetate/hexanes (2/1 ratio) afforded 5-(2-methoxy-phenyl)-pyrazin-2-ylamine (210 mg, 16%).
Reaction SMILES: C1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[CH:15]1[NH:19][CH2:18][CH2:17][S:16]1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(N(CC)CC)C>[Cl:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[C:9]=1[CH:15]1[N:19]([C:22](=[O:23])[CH2:21][Cl:20])[CH2:18][CH2:17][S:16]1
Reactant: Clc1cccc(Cl)c1C1NCCS1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(CCl)N1CCSC1c1c(Cl)cccc1Cl
Reaction time: 0.5 h

Procedure:
Twenty-three and five tenths (23.5) ml. of a benzene solution containing 5.9 g. of 2(2',6'-dichlorophenyl) thiazolidine was combined with 25 ml. of benzene and 2.8 g. of chloroacetyl chloride and the mixture stirred in an ice bath, while 2.6 g. of triethylamine was added dropwise. After standing for about 30 minutes the mixture was washed with water, separated, dried over magnesium sulfate and the benzene stripped off under vacuum. There was obtained a yield of 8 g. of an oil, the title compound, ND30 =1.6041.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=S.S(Cl)([Cl:14])(=O)=O>>[Cl:14][C:2]1[S:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=S(=O)(Cl)Cl
Reactant: S=c1[nH]c2ncccc2s1
Product: Clc1nc2ncccc2s1
Reaction time: 8 h
Yield: 39.8 %

Procedure:
The intermediate [1,3]thiazolo[4,5-b]pyridine-2(3H)-thione (644.0 mg, 3.83 mmol, dry powder) was treated with neat sulfuryl chloride (3.08 ml, 38.28 mmol) and allowed to stir at it overnight. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with 1N NaOH, followed by brine, and dried over Na2SO4. Concentration in vacuo gave the title compound (260.0 mg, 40%). LC/MS m/z 171.2 (MH+); retention time 1.55 min. 1H NMR (400 MHz, DMSO-d6) δ 7.58 (m, 1H), 8.62 (d, 1H), 8.78 (d, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8]C1C=C(CNCCCNCCCCNCCCN)C=CC=1O.O[C:32]1([CH3:58])[CH2:37][CH:36]([CH:38]([CH3:42])[CH2:39][C:40]#[N:41])[C:35]2[CH:43]=[CH:44][C:45]([CH:47]([CH2:49][CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH3:48])=[CH:46][C:34]=2[O:33]1.C(OCC)(=O)C>O1CCCC1>[NH2:41][CH2:40][CH2:39][CH:38]([CH:36]1[C:35]2[C:43]([OH:8])=[CH:44][C:45]([CH:47]([CH2:49][CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH3:48])=[CH:46][C:34]=2[O:33][CH:32]([CH3:58])[CH2:37]1)[CH3:42]
Reactant: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Reactant: CC(CCCc1ccccc1)c1ccc2c(c1)OC(C)(O)CC2C(C)CC#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1CC(C(C)CCN)c2c(O)cc(C(C)CCCc3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under anhydrous conditions and a nitrogen atmosphere, to a solution of 190 mg (5 mmole) lithium aluminum hydride in 50 ml tetrahydrofuran at 10° C. is added dropwise a solution of 1.885 g (5 mmole) dl-5-hydroxy-4-(1-methyl-2-cyanoethyl)-2-methyl-7-(5-phenyl-2-pentyl)-3,4-dihydro-2H-benzopyran in 25 ml of tetrahydrofuran. After the addition is complete, the mixture is stirred at room temperature for 6 hours. Ethyl acetate is added to consume the unreacted hydride. The reaction mixture is evaporated to dryness, the residue partitioned between water and methylene chloride and the organic layer dried over anhydrous magnesium sulfate. The solvent is evaporated to provide the title compound as the free base.