Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]1[CH2:21][CH2:20][CH2:19]1.O>C(O)C>[CH:18]1([CH2:17][O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: OCc1ccc(O)cc1
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: OCc1ccc(OCC2CCC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
A mixture of 4-(hydroxymethyl)phenol (3.20 g, 25.8 mmol), potassium carbonate (7.12 g, 51.6 mmol) and (bromomethyl)cyclobutane (3.75 mL, 33.6 mmol) in ethanol (50 mL) was stirred at 70° C. overnight. Water was added thereto, ethanol was evaporated under reduced pressure, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=19:1 to 13:7), and then purified by basic silica gel chromatography (hexane:ethyl acetate=19:1 to 13:7), and the solvent was evaporated to give the title compound (1.17 g, yield 23%) as an oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][N:51]1[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:54]6[CH2:55][CH2:56][CH2:57][N:51]([CH3:50])[CH2:52][CH2:53]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2C)c1
Reactant: CN1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCCN(C)CC4)c3)c2C)c1
Yield: 42 %

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-2-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL) with 1-methylhexahydro-1H-1,4-diazepine (30.4 μL., 0.00024 mol) and sodium triacetoxyborohydride (68 mg., 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. Purification was carried out on Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as a pale brown colored solid [48.3 mg (42%)]. LC-MS m/z 757.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(Cl)(Cl)[Cl:14]>>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1
Reactant: ClC(Cl)Cl
Reactant: Oc1cccc2cnc(Cl)nc12
Product: Oc1ccc(Cl)c2cnc(Cl)nc12
Temperature: 40 °C
Yield: 65 %

Procedure:
To a solution of 2-chloroquinazolin-8-ol (1 eq) in chloroform was added N-chlosuccinimide (1 eq) and the resulting mixture was heated to 40° C. for 2 h. The chlorination goes to completion giving 2,5-dichloroquinazolin-8-ol in 65% yield. 25% of the reaction was 2,7-dichloroquinazolin-8-ol and 15% of the reaction mixture was 2,5,8-trichloro quinazolin-8-ol. The reaction mixture was concentrated and the crude was purified by silica gel. The structures of the isomers were confirmed by 1H NMR and by LC/MS. ES/MS m/z 215 (MH+).
Reaction SMILES: C(=O)([O-])O.[Na+].Cl[C:7]1[N:12]=[CH:11][C:10]([C:13]([O:15]C)=[O:14])=[CH:9][N:8]=1.CC1(C)C(C)(C)OB([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=2)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:34]([O:33][C:31]([N:28]1[CH2:27][CH:26]=[C:25]([C:7]2[N:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][N:12]=2)[CH2:30][CH2:29]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ncc(C(=O)O)cn2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
Saturated aqueous sodium hydrogen carbonate solution (25.00 ml) was added to methyl 2-chloropyrimidine-5-carboxylate (0.863 g, 5 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (1.855 g, 6.00 mmol), palladium(II) acetate (0.056 g, 0.25 mmol) and triphenylphosphine (0.262 g, 1.00 mmol) in 1,2-dimethoxyethane (25.00 ml) at 25° C. under nitrogen. The resulting mixture was stirred at 80° C. for 4 h. The cooled reaction mixture was taken up in water (50 mL), washed with EtOAc (50 mL) and then the aqueous layer was acidified to pH1 with 2N HCl. The aqueous layer was extracted with EtOAc (3×25 mL) and the combined organics washed with brine, dried over MgSO4 and concentrated under reduced pressure to afford 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylic acid (1.280 g, 84%) as a yellow solid. This was used directly with no further purification.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Br:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][NH:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Br:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Brc1cccc2c1CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(Br)cccc21
Yield: 72.3 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 402 mg of 4-bromoindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of dimethylformamide. 303 mg of 2-[2-(4-bromo-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].Cl.[CH3:13][O:14][NH2:15].O.O.O.C([O-])(=O)C.[Na+]>CO.O>[CH3:13][O:14][N:15]=[C:4]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CON=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.1 %

Procedure:
In 3.8 l of methanol was dissolved 176 g of isatin while heating, and a solution of 100 g of O-methylhydroxylamine hydrochloride and 136 g of sodium acetate trihydrate in 400 ml of water was added thereto. The resulting mixture was stirred at room temperature for 10 minutes, followed by concentration. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate, dried over anhydrous sodium sulfate, and concentrated to give 192 g (91%) of 3-methoxyiminoindolin-2-one. The resulting crude product was used in the subsequent reaction without being purified.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([CH2:10]I)[O:8][C@@H:7]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2].C1CN2C(=NCCC2)C1>CC#N>[C:1]([O:4][C@H:5]1[C:9](=[CH2:10])[O:8][C@H:7]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CI
Agent: C1CN=C2CCCN2C1
Solvent: CC#N
Product: C=C1O[C@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.9 %

Procedure:
To an CH3CN (40 mL) solution of 7 (5.5 g, 13.95 mmol) was added DBN (6.9 mL, 55.81 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 17 h. After neutralization with AcOH, the reaction mixture was evaporated to dryness. The residue was partitioned between CHCl3/saturated aqueous NaHCO3 (200 mL×3/50 mL). Silica gel column chromatography (hexane/EtOAc=2/1-1/1) of the organic layer gave 8 (3.34 g, 90%) as a foam: 1H NMR (CDCl3) δ: 1.96 (3H, d, J6,Me=1.3 Hz, Me), 2.06 (3H, s, Ac), 2.21 (1H, dt, Jgem=15.2 Hz, J1′,2′a=J2′a,3′=2.7 Hz, H-2′a), 2.83 (1H, dt, Jgem=15.2 Hz, J1′,2′b=J2′b,3′=7.1 Hz, H-2′b), 4.51 (1H, dd, Jgem=2.4 Hz, J3′,5′a=0.8 Hz, H-5′a), 4.73 (1H, dd, Jgem=2.4 Hz and J3′,5′b=0.7 Hz, H-5′b), 5.70-5.73 (1H, m, H-3′), 6.44 (1H, dd, J1′,2′a=2.7 Hz and J1′,2′b=7.1 Hz, H-1′), 7.25 (1H, d, J6,Me=1.3 Hz, H-6), 8.54 (1H, br, NH); FAB-MS m/z 267(M++H).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][N:6]([CH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[CH3:7])[CH3:2].CCN=C=NCCCN(C)C.Cl.[NH2:32][C:33]1[CH:55]=[CH:54][C:53]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)=[CH:52][C:34]=1[C:35]([NH:37][C:38]1[N:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[C:46]([CH3:51])[CH:45]=2)=[CH:40][N:39]=1)=[O:36]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:18]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([CH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:32][C:33]1[CH:55]=[CH:54][C:53]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)=[CH:52][C:34]=1[C:35]([NH:37][C:38]1[N:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[C:46]([CH3:51])[CH:45]=2)=[CH:40][N:39]=1)=[O:36])=[O:14])[CH3:7])[CH3:19]
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3N)nc2)cc1C
Reactant: CCN(CC)CCN(C)Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCN(C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ncc(-c3ccc(C)c(C)c3)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
Into a 10-mL round bottom flask, was placed a solution of 3-(((2-(diethylamino)ethyl)(methyl)amino)methyl)benzoic acid (118.8 mg, 0.45 mmol, 1.50 equiv) in dichloromethane (24 mL), EDC.HCl (171.6 mg, 0.90 mmol, 3.00 equiv), 4-dimethylaminopyridine (182.4 mg, 1.49 mmol, 5.00 equiv), and 2-amino-N-(5-(3,4-dimethylphenyl)pyrimidin-2-yl)-5-(piperidin-1-yl)benzamide (120 mg, 0.29 mmol, 1.00 equiv). The resulting solution was stirred for 8 h at 25° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 139.2 mg (62%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.37 (s, 1H), 11.30 (s, 1H), 8.75 (d, J=6 Hz, 2H), 8.22 (d, J=9 Hz, 1H), 8.054 (s, 1H), 7.93 (d, J=6.3 Hz, 1H), 7.68˜7.60 (m, 2H), 7.53 (s, 1H), 7.31˜7.20 (m, 3H), 7.15 (d, J=7.2 Hz, 1H), 3.40˜3.12 (m, 13H), 2.59 (s, 2H), 2.32˜2.27 (m, 4H), 2.16 (s, 3H), 1.68 (m, 4H), 1.58˜1.57 (m, 2H), 1.21˜1.16 (m, 6H). MS (ES, m/z): 648 [M−H]+.
Reaction SMILES: ClC1C2C(=O)C3C(=CC=C(OC)C=3)NC=2C([N+]([O-])=O)=CC=1.[Cl:22][C:23]1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=[CH:30][CH:31]=[C:32](OC)[CH:33]=3)[N:28]([CH3:40])[C:27]=2[C:26]([N+:41]([O-:43])=[O:42])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH3:40])[C:27]=2[C:26]([N+:41]([O-:43])=[O:42])=[CH:25][CH:24]=1
Reactant: COc1ccc2c(c1)c(=O)c1c(Cl)ccc([N+](=O)[O-])c1n2C
Agent: COc1ccc2[nH]c3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Product: Cn1c2ccccc2c(=O)c2c(Cl)ccc([N+](=O)[O-])c21

Procedure:
In the same manner, 7.62 g (0.025 mol) of 1-chloro-7-methoxy-4-nitro-9(10H)-acridinone was converted to 5.05 g (63%) of 1-chloro-7-methoxy-10-methyl-4-nitro-9(10H)-acridinone, mp 235-240 degrees after recrystallization from toluene.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])[C:2]([CH3:4])=[O:3].[C:11](OC(=O)C)(=[O:13])[CH3:12]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C>[C:11]([O:3][C:2](=[CH2:4])[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])(=[O:13])[CH3:12]
Reactant: CCCCOC(=O)C(C)=O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: C=C(OC(C)=O)C(=O)OCCCC
Temperature: 120 °C
Reaction time: 25 h
Yield: 67.1 %

Procedure:
Next, in a mixture of the obtained butyl pyruvate (235 g, 1.6 mol) and acetic anhydride (333 g, 3.3 mol), p-toluenesulfonic acid monohydrate (5 g) was added. Then, the mixture was stirred under a nitrogen gas stream at 120° C. for 25 hours to obtain a second reaction solution. Next, acetic acid generated by a reaction with excess acetic anhydride under reduced pressure (5 mmHg) was removed from the second reaction solution. Thereafter, the residue was purified by reduced pressure distillation (2 mmHg, 56 to 63° C.) to obtain butyl α-acetoxyacrylate (200 g, yield 67%).
Reaction SMILES: Cl[C:2]1[N:18]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][N:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)=[CH:28][CH:29]=4)[N:18]=3)[CH:9]=[CH:8][CH:7]=2)[CH:13]=1
Reactant: Clc1nc2c(NCc3cccnc3)cccn2n1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: c1cncc(CNc2cccn3nc(Nc4ccc(OCCN5CCCC5)cc4)nc23)c1

Procedure:
N(8)-Pyridin-3-ylmethyl-N(2)-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-pyridin-3-ylmethyl-amine (75.0 mg, 0.289 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (67.0 mg, 0.325 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (33.0 mg, 0.0604 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.031 g, 25%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.67 (s, 1H), 8.56 (d, J=4.2 Hz, 1H), 7.83 (d, J=6.6 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.31-7.25 (m, 1H), 6.92 (d, J=8.8 Hz, 2H), 6.66 (t, J=7.1 Hz, 1H), 6.56 (s, 1H), 6.31 (d, J=7.6 Hz, 1H), 5.18 (t, J=5.4 Hz, 1H), 4.51 (d, J=5.6 Hz, 2H), 4.10 (t, J=6.0 Hz, 2H), 2.89 (t, J=5.9 Hz, 2H), 2.66-2.59 (m, 4H), 1.85-1.77 (m, 4H). MS=430 (MH)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)([CH3:9])[CH3:8]>CO.[Ni]>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:9])[CH3:8]
Reactant: COCCOCC(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Product: COCCOCC(C)(C)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A suspension of 1-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-4-nitro-benzene (8.1 g, 32 mmol) and Raney Ni (1 g) in MeOH (50 mL) was stirred under H2 (1 atm) at room temperature for 1 h. The catalyst was filtered off and the filtrate was concentrated to obtain 4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenylamine (5.5 g, 77%).
Reaction SMILES: [S:1](Br)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(CC)CC.[C:19]([C:23]1[C:24]([SH:37])=[CH:25][C:26]([CH3:36])=[C:27]([O:29][S:30](=[O:35])(=[O:34])[N:31]([CH3:33])[CH3:32])[CH:28]=1)([CH3:22])([CH3:21])[CH3:20]>C(Cl)(Cl)(Cl)Cl>[C:19]([C:23]1[CH:28]=[C:27]([O:29][S:30](=[O:34])(=[O:35])[N:31]([CH3:32])[CH3:33])[C:26]([CH3:36])=[CH:25][C:24]=1[S:37][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(S)c(C(C)(C)C)cc1OS(=O)(=O)N(C)C
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OS(=O)(=O)N(C)C)cc2C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer and addition funnel were added tosyl bromide (1.64 g, 7.0 mmol), CCl4 (25 mL), and NEt3 (0.98 mL, 7.0 mmol). The ensuing slurry was then cooled to 0° C. A solution of 1.07 g (3.5 mmol) of dimethyl-sulfamic acid 5-tert-butyl-4-mercapto-2-methyl-phenyl ester (prepared in Example TTT) in CCl4 (25 mL) was added dropwise to the slurry. Addition was complete in 1.0 hour. After addition was complete, the ice bath was removed and the reaction was stirred at room temperature overnight. The mixture was diluted with CH2Cl2, washed with brine, dried (MgSO4), and concentrated. The residue was taken up in a small amount of EtOAc and triturated with hexane. The product was filtered and dried under high vacuum to yield the title compound. 1H NMR (CDCl3) δ 1.15 (s, 9 H), 2.23 (s, 3 H), 2.37 (s, 3 H), 3.02 (s, 6 H), 7.19 (d, 2 H), 7.22 (s, 1 H), 7.33 (s, 1 H), 7.40 (d, 2 H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[CH2:30][S:29]1.[C:43]([O:47][C:48]([NH:50][C:51]1([CH:54]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)[C:55](O)=[O:56])[CH2:53][CH2:52]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl>[Cl:64][C:61]1[CH:62]=[CH:63][C:58]([CH:54]([C:51]2([NH:50][C:48](=[O:49])[O:47][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:52][CH2:53]2)[C:55]([N:40]2[CH2:41][CH2:42][N:37]([C:35]3[C:36]4[C@H:28]([CH3:27])[S:29][CH2:30][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:38][CH2:39]2)=[O:56])=[CH:59][CH:60]=1
Reactant: C[C@@H]1SCc2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)NC1(C(C(=O)O)c2ccc(Cl)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1SCc2ncnc(N3CCN(C(=O)C(c4ccc(Cl)cc4)C4(NC(=O)OC(C)(C)C)CC4)CC3)c21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
HBTU (0.097 mmol, 47 mg) was added to a solution of (S)-5-methyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (30 mg, 0.097 mmol) and 2-(1-(tert-butoxycarbonylamino)cyclopropyl)-2-(4-chlorophenyl)acetic acid (0.097 mmol) in DCM (5 mL) and TEA (5 mL). The mixture was stirred at room temperature for 6 hours. The solvent was removed, and the residue was subject to column chromatography, eluted by DCM/MeOH (50:1) to give tert-butyl 1-(1-(4-chlorophenyl)-2-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)cyclopropylcarbamate LCMS: 544.0 [M-Boc+H+] (APCI+); Rf: 3.49 min. The tert-butyl 1-(1-(4-chlorophenyl)-2-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)cyclopropylcarbamate was deprotected using procedures described previously to give 2-(1-aminocyclopropyl)-2-(4-chlorophenyl)-1-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)ethanone. Rf: 2.24 min.
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[CH:8][C:7](=[O:11])[N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:5]=2[S:4][C:3]=1[C:19]#[N:20].[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=1[CH3:29].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:6]1[C:7](=[O:11])[CH:8]=[CH:9][C:10]2[C:2]([NH:26][C:25]3[CH:27]=[CH:28][C:22]([F:21])=[C:23]([CH3:29])[CH:24]=3)=[C:3]([C:19]#[N:20])[S:4][C:5]1=2
Reactant: Cc1cc(N)ccc1F
Reactant: N#Cc1sc2c(ccc(=O)n2-c2ccccc2Cl)c1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2c(C#N)sc3c2ccc(=O)n3-c2ccccc2Cl)ccc1F
Yield: 28.5 %

Procedure:
A mixture of Example 13 (500 mg, 1.37 mmol), 4-fluoro-3-methylaniline (206 mg, 1.64 mmol), Cs2CO3 (625 mg, 1.92 mmol), BINAP (85 mg, 0.37 mmol, 10 mol %) and Pd2(dba)3 (63 mg, 0.0685 mmol, 5 mol %) in toluene was heated at reflux for 18 h. A second charge of BINAP (42 mg, 5 mol %) and tris(dibenzylideneacetone)dipalladium(0) (31.5 mg, 2.5 mol %) was added and the mixture heated at reflux for a further 4 days. The mixture was partitioned between DCM (100 mL) and H2O (50 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (silica, 10% EtOAc in DCM) gave the title compound as an off-white solid (160 mg, 28%). δH (DMSO-d6) 9.39 (1H, s), 8.17 (1H, d, J 9.7 Hz), 7.87 (1H, dd, J 1.7, 7.9 Hz), 7.79 (1H, dd, J 2.1, 7.9 Hz), 7.75-7.66 (2H, m), 7.24-7.12 (3H, m), 6.71 (1H, d, J 9.7 Hz), 2.29 (3H, d, J 1.7 Hz). LCMS (ES+) RT 3.63 minutes, 410 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].Cl.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH2:20])=[O:19])=[CH:13][CH:12]=1>C(#N)C>[CH3:3][C:2]([NH:20][C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)=[O:19])([CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=C(C)c1ccccc1
Reactant: Cc1ccc(NC(N)=O)cc1
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(NC(=O)NC(C)(C)c2ccccc2)cc1
Temperature: 20 °C

Procedure:
30 ml. of α-methylstyrene was placed in a 200 ml. reactor, and while externally cooling with ice, anhydrous hydrochloric acid was introduced at 0 to 10° C. When the weight of the mixture increased by 1.8 g, the introduction of the hydrochloric acid was stopped. 11.3 g of p-tolylurea and 40 parts of acetonitrile were added, and with stirring, the mixture was heated. After heating it for 4 hours at 40 ± 2° C., the reaction mixture was maintained at 20° C. for 3 days. The precipitated crystals were collected, and recrystallized from 70% methanol to afford 13.5 g of N-(α,α-dimethylbenzyl)-N'-(p-tolyl)urea having a melting point of 203° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])=[CH:4][CH:3]=1
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccc(Br)cc3)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccc(Br)cc4)oc23)[C@@H]1CO

Procedure:
Compound of example 77 (0.61 g, 1.29 mmol) was subjected to demethylation with pyridine hydrochloride (6.1 g, 52.81 mmol) as described in example 17, afforded the two title compounds which were separated using column chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-])=O)=[C:6]([CH:13]=1)[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8].CC1C=CC=C([N+]([O-])=O)C=1C(OCC=C)=O>>[NH2:14][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:13][C:6]=1[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8]
Reactant: C=CCOC(=O)c1cc(C)ccc1[N+](=O)[O-]
Agent: C=CCOC(=O)c1c(C)cccc1[N+](=O)[O-]
Product: C=CCOC(=O)c1cc(C)ccc1N

Procedure:
The above nitro compound was reduced by the method described in example 6, for the reduction of allyl 2-methyl-6-nitrobenzoate to give allyl 2-amino-5-methylbenzoate.