Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:23])[C:10](=[O:22])[CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>>[NH2:7][C:8]1[N:9]([CH3:23])[C:10](=[O:22])[CH2:11][C@:12]([C:15]2[CH:16]=[C:17]([NH:21][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=3)[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: CN1C(=O)C[C@@](C)(c2cccc(N)c2)N=C1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cccnc1
Product: CN1C(=O)C[C@@](C)(c2cccc(NC(=O)c3cccnc3)c2)N=C1N

Procedure:
The coupling of [(S)-4-(3-amino-phenyl)-1,4-dimethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester from experiment F1 and nicotinic acid followed by deprotection of the intermediate yielded the title compound as a colourless solid. MS (ESI): m/z=338.4 [ M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)C>[C:11]1([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:31]4[CH2:32][CH2:33][CH:28]([N:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[CH2:29][CH2:30]4)=[N:7][N:6]3[C:8]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ccc2nc(-c3ccccc3)c(-c3ccncc3)n2n1
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CCO
Product: c1ccc(-c2nc3ccc(N4CCC(N5CCCC5)CC4)nn3c2-c2ccncc2)cc1
Temperature: 155 °C
Yield: 27 %

Procedure:
A mixture of 4.03 g (13.1 mmol) of 6-chloro-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine and 4.4 g (29 mmol) of 4-pyrrolidin-1-ylpiperidine in 50 mL of ethanol is heated at 155° C. for 4 hours. After cooling, the solvent is evaporated off under reduced pressure and the residue is chromatographed on silica gel, eluting with a mixture of dichloromethane and methanol (93:7). The product is then recrystallized from 40 mL of methanol to give 1.5 g of yellow crystals after drying under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:21](OCC)=[O:22])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:21][OH:22])([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C1(Cc2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(CO)(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.5 %

Procedure:
To a stirring solution (+/−)-N-(t-butoxycarbonyl)-3-(carboethoxy)-3-(phenylmethyl)-piperidine (200 mg, 0.58 mmol) in dry toluene (20 mL) at −78° C. was added a 1.5 M solution of diisobutylaluminium hydride in toluene (2.0 mL). After 6 h, the reaction was warmed to room temperature and quenched by the addition of 1M HCl (50 mL). The reaction was extracted with EtOAc (4×40 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and conc. in vacuo to an oil. The oil was purified by flash chromatography (SiO2, 7–20% EtOAc in hexanes) to yield 86 mg of the product as a colorless oil. MS (ESI) 306 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][CH:9]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH2:8]2)([O:3]C)=[O:2].[OH-].[Na+]>CO.O>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][CH:9]([N:16]([CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH3:22])[CH2:8]2)([OH:3])=[O:2]
Reactant: CCCN(CCC)C1Cc2cc(OC)c(C(=O)OC)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCN(CCC)C1Cc2cc(OC)c(C(=O)O)cc2C1

Procedure:
A solution of 5-carbomethoxy-6-methoxy-2-(di-n-propylamino)indan (Example 57) in methanol/water is hydrolyzed with sodium hydroxide. After work-up and purification, the title compound is obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:40])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:17])([F:16])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:40])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C(F)(F)F)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C(F)(F)F)c3)c1)=N2

Procedure:
The title compound was prepared from (5-methyl-2-{3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M245) (0.28 g, 0.48 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (220 mg, 99%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34].[Br:35][CH2:36][CH2:37][CH2:38]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:35][CH2:36][CH2:37][CH2:38][O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: OCCCBr
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
Diethyl azodicarboxylate (3.9 ml, 24.5 mmol) was added in portions to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (5 g, 16.3 mmol), (prepared as described for the starting material in Example 12), 3-bromo-1-propanol (2.21 ml, 24.5 mmol) and triphenylphosphine (6.42 g, 24.5 mmol) in methylene chloride (50 ml). After stirring for 2 hours at ambient temperature, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride followed by methylene chloride/methanol (95/5) to give 7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (6 g, 86%).
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[Br:20]Br.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>O>[Br:20][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])[C:11]([OH:13])=[O:12]
Reactant: O=C(O)CCCCCN1C(=O)c2ccccc2C1=O
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)C(Br)CCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
Combine 6-phthalimidohexanoic acid (12.7 g, 48 mmol) and dry red phosphorous (1.95 g, 63 mmol). Cool in an ice bath and add dropwise bromine (12.7 mL, 246 mmol). Warm to room temperature and then heat to 80° C. After 3 hours, cool the reaction mixture to ambient temperature, pour into water (300 mL) containing sodium bisulfite, and neutralize using solid sodium bicarbonate and extract with diethyl ether (about 150 mL). Acidify the aqueous layer with concentrated hydrochloric acid give a solid. Collect the solid by filtration and dry to give the title compound (15 g, 91.5% yield, 73.2% for both steps).
Reaction SMILES: CS([C:5]1[N:12]=[C:11]([CH2:13][O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])(=O)=O.[CH2:25]([Mg]Br)[CH3:26].CCOCC>>[CH2:25]([C:5]1[N:12]=[C:11]([CH2:13][O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[CH3:26]
Reactant: CC(C)[Si](OCc1ccc(C#N)c(S(C)(=O)=O)n1)(C(C)C)C(C)C
Reactant: CC[Mg]Br
Solvent: CCOCC
Product: CCc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C#N

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 24 (24c) using 2-(methylsulfonyl)-6-{[(triisopropylsilyl)oxy]methyl}nicotinonitrile (0.78 g, 2.1 mmol) that was obtained in Example 24 (24b) and a 3.0 M solution of ethylmagnesium bromide in ether (1.4 ml, 4.2 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 1:9) as the eluent to afford the title compound (0.65 g) in a yield of 97% as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[S:26]1[CH:30]=[CH:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:34]([CH2:35][NH2:36])[C:27]1=2.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CC#N.CN(C)C=O>[S:26]1[CH:30]=[CH:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:34]([CH2:35][NH:36][C:22]([C:10]3[N:11]=[C:12]4[N:17]([C:18](=[O:19])[C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:16][CH2:15][O:14][C:13]4([CH3:20])[CH3:21])=[O:24])[C:27]1=2
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1cccc2ccsc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1(C)OCCn2c1nc(C(=O)NCc1cccc3ccsc13)c(OCc1ccccc1)c2=O
Temperature: 23 °C
Reaction time: 60 h
Yield: 220.6 %

Procedure:
To a solution of intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid (0.200 g, 0.60 mmol) in CH3CN:dimethylformamide (30 mL: 5 mL) was added intermediate 139, benzo[b]thiophen-7-ylmethanamine hydrochloride (0.069 g, 0.266 mmol), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBOP) (0.347 g, 0.670 mmol) and diisopropylethylamine (420 μL, 2.40 mmol). The reaction mixture was stirred at 23° C. for 60 h. The solvents were then removed in vacuo and 1N HCl (50 mL) added. This was extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on a Biotage system using a silica gel column with hexane:ethyl acetate (1:1) to (1:5) gradient as eluent to afford the title compound (0.279 g, 87% yield): 1H NMR (400 MHz, DMSO-d6) δ: 9.11 (1H, dd, J=5.6 Hz), 7.81 (1H, m), 7.77 (1H, d, J=5.6 Hz), 7.52 (1H, d, J=5.6 Hz), 7.48-7.26 (6H, m), 5.09 (2H, s), 4.67 (2H, d, J=5.2 Hz), 4.04 (2H, m), 3.90 (2H, m), 1.58 (6H, s). LCMS (M+H)+ m/z 476.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:45])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:42]=3)=[C:18]([O:43][CH3:44])[CH:17]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:45])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:42]=3)=[C:18]([O:43][CH3:44])[CH:17]=2)[CH2:10][CH2:9]1
Reactant: COc1cc(C(=O)N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)N[C@H]2CC[C@@H](N)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1.5 h

Procedure:
A mixture of 0.046 g (0.07 mmole) of cis-{4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (I-97), 2.25 mL of dichloromethane and 0.25 mL of trifluoroacetic acid was stirred for 1.5 hours and then concentrated under reduced pressure. The residue was diluted with methanol and neutralized with 1.0 M sodium hydroxide at 0 degrees. The methanol solution was purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient, 1:99-90:10) to give 0.0226 g of cis-N-(4-amino-cyclohexyl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-98).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:34])[NH:7][C@H:8]1[C:11](=[O:12])[N:10](C2C=CC(OC)=CC=2)[C@H:9]1[CH2:21][O:22][N:23]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])[CH3:3].N1C=CC=CC=1.Cl[S:42]([CH2:45][C:46]([O:48][CH3:49])=[O:47])(=[O:44])=[O:43]>C1COCC1.C(OCC)(=O)C>[CH3:49][O:48][C:46](=[O:47])[CH2:45][S:42]([NH:23][O:22][CH2:21][C@H:9]1[C@@H:8]([NH:7][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:34])[C:11](=[O:12])[NH:10]1)(=[O:44])=[O:43]
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: COc1ccc(N2C(=O)[C@H](NC(=O)OC(C)(C)C)[C@@H]2CON2C(=O)c3ccccc3C2=O)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)CS(=O)(=O)NOC[C@@H]1NC(=O)[C@@H]1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of the oxyamine produced in Example 1 (495 mg, 2.1 mmol) in dry THF containing pyridine (1.1 eq.) was added ClSO2CH2CO2CH3 and the solution was stirred for 1 hour at 0° C. The reaction mixture was diluted with ethyl acetate and washed with 1N HCl, 5% sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. The product was purified by flash chromatography (ethyl acetate-hexane, 1:2) to afford 426 mg (54%) of [[[[cis-3-[[(1,1-dimethylethoxy)carbonyl]amino]-4-oxo-2-azetidinyl]methoxy]amino]sulfonyl]acetic acid methyl ester: mp 128°-129° C. (CH2Cl2); IR (KBr) 3340, 3210, 2975, 1780, 1740, 1685, 1525, and 1160 cm-1 ; NMR (DMSO-d6) δ 1.40 (9H, s), 3.75 (3H, s), 3.90 (1H, m), 4.00 (2H, m), 4.34 (1H, d, J=15 Hz), 4.42 (1H, d, J=15 Hz), 4.94 (1H, d, J=9, 6 Hz), 7.68 (1H, d, J=9 Hz, exchangeable), 8.44 (1H, s, exchangeable).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:35][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[C:15]([O:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]4)=[N:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[C:6]=1[CH3:36])=[O:4].[OH-].[Na+].[OH-].[Li+].Cl>CO>[C:31]([O:30][C:28]([NH:27][CH:24]1[CH2:25][CH2:26][CH:21]([O:20][C:15]2[C:14]([NH:13][C:12]3[C:7]4[C:6]([CH3:36])=[C:5]([C:3]([OH:4])=[O:2])[S:35][C:8]=4[N:9]=[CH:10][N:11]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:22][CH2:23]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)c1sc2ncnc(Nc3cccnc3OC3CCC(NC(=O)OC(C)(C)C)CC3)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCC(NC(=O)OC(C)(C)C)CC3)c12
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 7 g 4-[2-(4-tert-butoxycarbonylamino-cyclohexyloxy)-pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and 4M sodium hydroxide solution (60 ml) and 500 mg lithium hydroxide in 60 ml MeOH was stirred at 80° C. for 5 hours. To the reaction mixture were added 65.2 ml 4M hydrochloric acid and the mixture was concentrated afterwards. The residue was triturated with water. The solid was isolated by filtration, washed with water and dried in a desiccator.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: Oc1ccc(CNc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(CNc2ccc(Cl)cc2)cc1
Yield: 55.1 %

Procedure:
A mixture of 500 mg of 4-(4-chloroanilinomethyl)phenol, 632 mg of ethyl 2-bromo-2-methylpropionate, 7.5 ml of methyl isobutyl ketone and 448 mg of potassium carbonate is refluxed under heating for 6 hours. The insolubles are filtered off from the reaction mixture, and the filtrate is washed with water, dried and concentrated. The residue (730 mg) is purified by column chromatography, using 22 g of silica gel and chloroform as a developer to give 410 mg of ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionate, mp 58° to 60° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:3]1=2.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][C:24]=2[O:35][CH3:36])[C:19]([Cl:37])=[CH:18][N:17]=1>>[Cl:37][C:19]1[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:25][C:24]=2[O:35][CH3:36])=[N:21][C:16]([NH:13][C:9]2[C:4]3[O:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=3[CH:12]=[CH:11][CH:10]=2)=[N:17][CH:18]=1
Reactant: CC1(C)CCCOc2c(N)cccc21
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2cccc3c2OCCCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared from 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 179. Product was isolated as a tan solid (78 mg, 80%). LCMS (m/e) 510 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.06 (s, 1H), 7.82 (m, 2H), 7.46 (dm, 1H, J=9 Hz), 6.84 (d, 1H, J=8 Hz), 6.75 (t, 1H, J=8 Hz), 6.68 (s, 1H), 6.52 (d, 1H, J=9 Hz), 3.91 (m, 2H), 3.77 (d, 7H), 3.16 (m, 4H), 1.96 (m, 2H), 1.60 (m, 2H), 1.30 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CC([O-])(C)C.[Na+]>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].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>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
A suspension of 1-bromo-4-chlorobenzene (500 mg, 2.63 mmol, 1.00 equiv), t-butyl piperazine-1-carboxylate (725 mg, 3.90 mmol, 1.50 equiv), BINAP (48.6 mg, 0.08 mmol, 0.03 equiv), Pd2(dba)3 (23.9 mg, 0.03 mmol, 0.01 equiv), and NaOt-Bu (780 mg, 8.12 mmol, 3.00 equiv) in toluene (20 mL) was placed in a 50-mL round bottom flask, stirred overnight at 100° C. in an oil bath, then concentrated under vacuum. Purification via silica gel column (PE/EA (50:1)) yielded 360.6 mg (46%) of t-butyl 4-(4-chlorophenyl)piperazine-1-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([S:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[CH:26][N:25]=[C:24]4[CH3:28])=[CH:19][CH:18]=3)[CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].[OH-:29].[K+]>C(O)(C)(C)C>[F:15][C:13]1[CH:12]=[C:11]([S:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[C:24]3[CH3:28])=[CH:19][CH:18]=2)[CH:10]=[C:9]([C:3]2([C:1]([NH2:2])=[O:29])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH:14]=1
Reactant: Cc1nccn1-c1ccc(Sc2cc(F)cc(C3(C#N)CCOCC3)c2)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1nccn1-c1ccc(Sc2cc(F)cc(C3(C(N)=O)CCOCC3)c2)cc1
Yield: 31.2 %

Procedure:
To a solution of 4-cyano-4-[5-fluoro-3-[4-(2-methylimidazol-1-yl)phenylthio ]phenyl]-3,4,5,6-tetrahydro-2H-pyran (Example 25, 1.71 g, 4.36 mmol) in tert-butanol (20 ml) was added powdered potassium hydroxide (85%, 860 mg, 13 mmol). The resulting mixture was heated at reflux temperature for 4 h, cooled and concentrated in vacuo. Water (50 ml) was added and the precipitates were collected by filtration and washed with 50 ml of ethyl acetate. After drying in vacuo, 560 mg (31%) of the titled compound was obtained as a yellow powder.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]2[C:11]([NH2:28])=[N:12][CH:13]=[C:14]([C:16]3[N:20]([CH3:21])[N:19]=[C:18]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:17]=3)[N:15]=2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:29][C@@H:30]([CH3:35])[CH2:31][C:32](O)=[O:33]>>[NH2:28][C:11]1[N:12]=[CH:13][C:14]([C:16]2[N:20]([CH3:21])[N:19]=[C:18]([CH:22]3[CH2:23][CH2:24][N:25]([C:32](=[O:33])[CH2:31][C@@H:30]([OH:29])[CH3:35])[CH2:26][CH2:27]3)[N:17]=2)=[N:15][C:10]=1[C:8]1[O:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1
Reactant: Cn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Reactant: C[C@H](O)CC(=O)O
Product: C[C@H](O)CC(=O)N1CCC(c2nc(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n(C)n2)CC1
Yield: 68.2 %

Procedure:
Using a similar procedure as Example 4, 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine was reacted with (S)-3-hydroxybutanoic acid to afford the title compound (167 mg, 68.2%) as a pale yellow solid. 1H NMR Spectrum: (CDCl3) 1.24 (3H, d), 1.52 (9H, s), 1.85 (2H, m), 2.10 (2H, m), 2.35 (1H, dd), 2.55 (1H, d), 2.90 (1H, m), 3.05 (1H, m), 3.20 (1H, m), 3.90 (1H, m), 4.25 (1H, m), 4.31 (3H, s), 4.6 (1H, m), 9.03 (1H, s); Mass Spectrum [M+H]+=470.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH2:19][CH3:20]>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11])[CH2:19][CH3:20]
Reactant: CCCI
Reactant: O=C1CCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1cccc2c1CCC2=O

Procedure:
To a suspension of 4-hydroxy-1-indanone (1.0 g, 6.75 mmol) in acetone (30 mL) was added potassium carbonate (2.8 g, 20.24 mmol) and propyl iodide (0.72 mL, 7.42 mmol) and the reaction mixture was heated to reflux for about 7 hours. The reaction was cooled, concentrated under vacuum and partitioned between water and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried (Na2SO4), filtered and concentrated under vacuum and the residue was purified by flash column chromatography on silica gel using dichloromethane as the mobile phase to provide the desired product. MS (APCI): m/z 191 (M+H)+.