Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[Cl:18][C:19]1[N:20]=[CH:21][N:22]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:23]=1[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][C:36]2[CH:41]=[C:40]([CH:42]=O)[CH:39]=[C:38]([Cl:44])[CH:37]=2)[C:29]=1[F:45])=[O:25]>C1COCC1.CCOC(C)=O>[Cl:18][C:19]1[N:20]=[CH:21][N:22]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:23]=1[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][C:36]2[CH:41]=[C:40](/[CH:42]=[CH:3]/[C:1]#[N:2])[CH:39]=[C:38]([Cl:44])[CH:37]=2)[C:29]=1[F:45])=[O:25]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C=O)c2)c1F
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(/C=C/C#N)c2)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (56.1 mg, 0.317 mmol) in THF (5 mL) at 0° C. was added potassium t-butoxide (1.0 M solution in THF) (0.317 ml, 0.317 mmol) and the mixture was stirred at 0° C. for 30 minutes. Next, 4-chloro-N-({4-chloro-3-[(3-chloro-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (165 mg, 0.288 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(E)-2-cyanoethenyl]phenyl}oxy)-2-fluorophenyl]methyl}-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (113 mg, 0.190 mmol, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (t, 1H), 7.95 (s, 1H), 7.54 (d, 2H), 7.41-7.48 (m, 1H), 7.36 (t, 1H), 7.23 (s, 1H), 6.97 (s, 1H), 6.58 (d, 1H), 5.47 (s, 2H), 4.45 (d, 2H), 3.36 (t, 2H), 0.72 (t, 2H), −0.12 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9](OC(=O)CC)(=O)[CH2:10][CH3:11].[CH2:18]([N:21]1[C@H:26]([CH3:27])[CH2:25][N:24]([C@H:28]([C:43]2[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=2)[C:46](Cl)=[O:47])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][Si](C(C)(C)C)(C)C)[CH:30]=2)[C@@H:23]([CH3:52])[CH2:22]1)[CH:19]=[CH2:20]>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:9][CH2:10][CH3:11].[CH2:18]([N:21]1[C@H:26]([CH3:27])[CH2:25][N:24]([C@H:28]([C:43]2[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=2)[C:46]([N:4]([C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[F:1])[CH2:9][CH2:10][CH3:11])=[O:47])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)[C@@H:23]([CH3:52])[CH2:22]1)[CH:19]=[CH2:20]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Reactant: CCC(=O)OC(=O)CC
Reactant: Nc1ccccc1F
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(CCC)c3ccccc3F)c2)C[C@H]1C
Product: CCCNc1ccccc1F

Procedure:
2-Fluoro-N-propylaniline [NMR (DMSO-d6, 200 MHz): δ 0.93 (t, J=7.4 Hz, 3H); 1.59 (m, 2H); 3.04 (q, 6.5 Hz, 2H); 5.33 (br m, 1H); 6.47-6.58 (m, 1H); 6.70 (t, J=8.1 Hz, 1H); 6.93-7.05 (m, 2H)] was prepared from 2-fluoroaniline and propionic anhydride, coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(2-fluorophenyl)-N-propylbenzamide as a white solid. NMR (DMSO-d6, 200 MHz): δ 0.9-1.05 (m, 9H); 1.5 (m, 2H); 1.7 (m, 1H); 2.05 (m, 1H); 2.3 (m, 1H); 2.5 (m, 2H); 2.7 (m, 1H); 2.85 (m, 1H); 3.2 (m, 1H); 3.7 (m, 2 H); 4.8 (br s, 1H); 5.1 (d, J=10 Hz, 1H); 5.2 (d, J=16 Hz, 1H); 5.8 (m, 1H); 6.5 (d, J=8 Hz, 1H); 6.6 (s, 1H); 6.65 (d, J=8 Hz, 1H); 7.0-7.4 (m, 9H); 9.3 (s, 1H). [α]D20 =+1.8° (abs ethanol, c=2.8). Calc. for C32H38FN3 O2HCl 0.25 H2O: C, 69.05; H, 7.15; N, 7.55; Cl, 6.37. Found: C, 68.94; H, 7.19; N, 7.57; Cl, 6.41. Mass spectrum (CI--CH4) m/e: 516 (M+1, 93%), 515 (M, 29%), 362 (26%), 153 (100%).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[C:22]([NH:24][CH2:25][CH2:26][N:27]1[C@H:32]([CH3:33])[CH2:31][NH:30][CH2:29][C@@H:28]1[CH3:34])=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH3:4].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[C:22]([NH:24][CH2:25][CH2:26][N:27]1[C@@H:32]([CH3:33])[CH2:31][N:30]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:29][C@H:28]1[CH3:34])=[O:23]
Reactant: CC(C)N=C=O
Reactant: C[C@@H]1CNC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)NC(=O)N1C[C@@H](C)N(CCNC(=O)[C@@H]2CCCCN2c2nc3ccccc3o2)[C@@H](C)C1
Product: N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Isopropylisocyanate (0.029 ml) was added to a solution of (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(cis)-2,6-dimethyl-1-piperazinyl]ethyl-2-piperidinecarboxamide (105 mg) [see Example 8] and potassium carbonate (37.5 mg) in acetonitrile (3 ml). The reaction mixture was stirred at room temperature for 5 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 94.6:5.6:0.8 changing to 93:7:1, by volume, dichloromethane:methanol: 0.88 aqueous ammonia solution to afford (cis)-4-[2-([(2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinyl]carbonylamino)ethyl]-N1-isopropyl-3,5-dimethyl-1-piperazinecarboxamide (72.8 mg) as a white solid.
Reaction SMILES: C1(C2C=CC([CH:8]=[O:9])=CC=2)CC1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[C:15]([Cl:23])[CH:14]=1.[Li]CCCC.CN(C=O)C>>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH:8]=[O:9])=[CH:14][C:15]=1[Cl:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: CC(C)(C)c1ccc(Br)cc1Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C=O)cc1Cl
Yield: 82 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 4-bromo-1-tert-butyl-2-chloro-benzene (200 mg, 0.81 mmol), nBuLi (0.66 ml, 1.6M solution in hexane, 1.05 mmol) and DMF (251 μl, 3.23 mmol). The isolated residue was purified by flash column chromatography (1:9 ether:pentane) to give 4-tert-butyl-3-chloro-benzaldehyde (130 mg, 82%) as a colorless liquid. 1H NMR (CDCl3, 300 MHz): δ 9.94 (s, 1H), 7.85 (d, J=2 Hz, 1H), 7.70 (dd, J=2 and 8 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 1.51 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:18][CH3:19])=[N:7][C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][C:3]=1[CH3:20].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C>[ClH:1].[ClH:1].[F:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([NH:18][CH3:19])=[N:7][C:8]([C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)=[N:9]3)=[CH:4][C:3]=2[CH3:20])[CH:25]=[CH:24][CH:23]=1
Reactant: CNc1nc(-c2cccnc2)nc2cc(Cl)c(C)cc12
Reactant: OB(O)c1cccc(F)c1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNc1nc(-c2cccnc2)nc2cc(-c3cccc(F)c3)c(C)cc12
Product: Cl

Procedure:
A mixture of 7-chloro-N,6-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine (400 mg, 1.40 mmol), 3-fluorophenylboronic acid (294 g, 2.10 mmol), Pd(OAc) (15.8 mg, 0.070 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (86.7 mg, 0.211 mmol), K3PO4 (900 mg, 4.23 mmol) in dioxane (10 mL) and water (2 mL) was stirred under reflux for 2.5 h. Ethyl acetate (20 mL) was added to the cooled mixture and a precipiate formed and was filtered. The solid was recrystallized from DMF and water to give the title compound as free form. The solid was suspended in ethyl acetate (10 mL) and 4N HCl in ethyl acetate (1.0 mL) was added. The resulting solid was subjected to sonication for 20 min, filtered and dried to give the title compound as the bis-110 salt (0.10 g, 18.7%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:24])[CH2:16][S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:24])[CH2:16][S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CSc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CSc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1-methyl-2-phenylsulfanyl-ethyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:3]1.[C:12]1([NH:18]N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CC(O)=O>[CH2:3]1[C:2]2[NH:18][C:12]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:7]=2[CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: NNc1ccccc1
Reactant: CC(=O)NC1CCCC(=O)C1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)NC1CCc2c([nH]c3ccccc23)C1
Reaction time: 3 h
Yield: 80.8 %

Procedure:
A stirred solution of 140.9 g (0.909 mol) of N-(3-oxocyclohexyl)acetamide in 900 ml of glacial HOAc was heated at 85°-95° C. while 98.2 g (0.909 mol) of phenylhydrazine was added dropwise during 1 hr. After an additional 3 hr at 95°±5°, the hot solution was poured into 5 l. of H2O. When the initially formed gum had solidified, the product was filtered, washed with 2.5 l. of H2O, then 2 l. of Et2O to give 167.6 g (81%) of a grey solid, mp 203°-206°. Recrystallization was best effected by dissolving the crude solid in boiling Me2CO (1 g/25 ml) and boiling down to 1 g/10 ml. The resulting yellow solid (133.5 g, mp 208°-209°) was recrystallized again from Me2CO to yield 111.8 g of white solid, mp 208°-209°. To remove Me2CO occluded by the crystalline solid, the product was further recrystallized from EtOH, 86% recovery of white solid, mp 208°-209°.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[N:11]=[C:12]2[C:17](=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)[CH:16]=[CH:15][CH:14]=[CH:13]2>C(O)C>[ClH:9].[CH:16]1[C:17]2[C:12](=[N:11][C:10]([NH:8][NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:23]3[C:18]=2[CH:19]=[CH:20][CH:21]=[CH:22]3)[CH:13]=[CH:14][CH:15]=1
Reactant: Clc1nc2ccccc2c2ccccc12
Reactant: NNc1ccccc1
Solvent: CCO
Product: Cl
Product: c1ccc(NNc2nc3ccccc3c3ccccc23)cc1
Temperature: 25 °C

Procedure:
Phenylhydrazine (1.3 g, 12 mmol) is dissolved in ethanol (50 ml) and admixed under argon with 6-chlorophenanthridine (A. G. Mikhailovskii, V. S. Shklyaev, Chem. Heterocycl. Comp. 1992, 445) (2.1 g, 10 mmol). The mixture is stirred under reflux for 16 h. After cooling to room temperature, the mixture is concentrated and the resulting precipitate is filtered off and washed with methyl tert-butyl ether. Yield: 2.6 g (82%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCCl>[C:20]1([S:26]([N:1]2[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])[CH2:4][C:3]3[CH:16]=[CH:17][CH:18]=[CH:19][C:2]2=3)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCNc2ccccc2C1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccccc2)c2ccccc2C1

Procedure:
To a stirred room temperature solution of tert-butyl 2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-ylcarbamate (39.3 mg, 0.15 mmol) in 1,2-dichloroethane (4 mL) was added benzenesulfonyl chloride (26.4 mg, 0.15 mmol). After 16 hours the mixture was evaporated to dryness to yield tert-butyl 1-(phenylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-ylcarbamate.
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13]([Cl:25])[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[C:11]2[C:10]([CH3:26])=[CH:9]1)=O)(C)(C)C.[Br:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31].CS(O)(=O)=O>O1CCOCC1.CO>[ClH:25].[Br:27][C:28]1[CH:29]=[C:30]([NH:31][C:13]2[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[O:18])=[C:11]3[C:10]([CH3:26])=[CH:9][NH:8][C:12]=23)[CH:32]=[CH:33][CH:34]=1
Reactant: Nc1cccc(Br)c1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)N3CCOCC3)c12
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c[nH]c2c(Nc3cccc(Br)c3)ncc(C(=O)N3CCOCC3)c12
Product: Cl
Temperature: 180 °C

Procedure:
A mixture of 7-chloro-3-methyl-4-(1-morpholin-4-yl-methanoyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester, 3-bromoaniline (56 μl), and methanesulfonic acid (33 μl) in 1,4-dioxane (2 ml) was heated under microwave conditions at 180° C. for 30 minutes. The solid mass obtained was dissolved in methanol, transferred to a round bottom flask and evaporated. The residue was dissolved in ethyl acetate and washed with 5% sodium hydrogen carbonate solution and water. The organic layer was dried (MgSO4) and evaporated to give an off-white solid. The solid was triturated with diethyl ether, filtered off and sucked dry. The solid was then dissolved in warm ethyl acetate (10 ml) and treated with a solution of 1M hydrochloric acid in diethyl ether (10 drops). The resultant solid precipitate was then filtered off, sucked dry then dried at 40° C. under vacuum to afford the title compound (58 mg).
Reaction SMILES: [O:1]=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)[CH:22]=2)[O:17][C:4]2([CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3]1.[ClH:30]>O1CCOCC1>[ClH:30].[O:29]=[C:27]1[O:26][N:25]=[C:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[O:17][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][C:2]3=[O:1])[NH:28]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3noc(=O)[nH]3)ccc1O2
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CC2(CCNCC2)Oc2ccc(-c3noc(=O)[nH]3)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 437 mg of tert-butyl 4-oxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate in 10 mL of 4N HCl in dioxane was stirred at rt for 1 d, the resultant white solid was filtered, and washed with ether. The collected white solid was dried in vacuo at 50° C. to give the intended compound as a colorless solid.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[C:8]([C:11]([NH2:13])=[O:12])[C:7]([CH3:14])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH2:21][C:22](OCC)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O(C)[Na].C(O)C>C(O)(=O)C.O>[C:1]([N:5]1[C:9]2=[N:10][C:22]([CH2:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][C:11](=[O:12])[C:8]2=[C:7]([CH3:14])[NH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(C(C)(C)C)c(N)c1C(N)=O
Reactant: CCOC(=O)Cc1ccccc1
Agent: CO[Na]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1[nH]n(C(C)(C)C)c2nc(Cc3ccccc3)nc(=O)c1-2
Yield: 35.1 %

Procedure:
A mixture of 1-tert-butyl-3-methyl-5-amino-1H-pyrazole-4-carboxamide (1.0 g, 5.1 mmol), ethyl phenylacetate (1.67 g, 10.2 mmol), NaOCH3 (1.74 g, 31 mmol) and ethanol (50 mL) was refluxed for about 3 days. The reaction mixture was stripped to dryness and then the residue was treated with water and then acidified with acetic acid. The product was collected by filtration, washed with water and dried to afford 0.53 g (35%) of 1-tert-butyl-3-methyl-6-(phenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one 1/5 hydrate, m.p. 196-197° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[H][H]>[Pd].CO>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)c1ccco1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CCCO1
Yield: 89.8 %

Procedure:
Methyl furoate (50.4 g.) is dissolved in 180 ml. of methanol. Thereafter 1 g. of 5 percent palladium-on-charcoal is added. This mixture is then hydrogenated at 1 to 3 atmospheres. After 45 hours 0.79 moles of hydrogen are consumed. The black mixture is then filtered through Celite using 50 ml. of methanol to wash the reaction flask and filter. Evaporation of the filtrate under reduced pressure at 40°14 45° C. bath temperature yields 51 g. of a yellow oil which is thereafter distilled, collecting that fraction boiling at 32°-35° C. Thereby, methyl tetrahydrofuroate (46.7 g.) is prepared.
Reaction SMILES: CS[C:3]1[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][NH2:24]>ClCCl>[C:11]([O:10][C:8]([N:7]1[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=[C:3]1[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:27]([F:28])=[C:20]([F:19])[CH:21]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: NCc1ccc(F)c(F)c1
Reactant: CSC1=N[C@@H]2CCCC[C@@H]2N1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(NCc2ccc(F)c(F)c2)=N[C@@H]2CCCC[C@@H]21
Temperature: 100 °C
Yield: 99.8 %

Procedure:
A mixture of intermediate 76 (200 mg, 0.740 mmol), 3,4-difluorobenzylamine (0.5 mL, 4.2 mmol) is heated at 100° C. (reaction block) overnight. The reaction mixture is cooled to RT. The reaction mixture is diluted with dichloromethane, washed with 0.1N HCl, and brine. The solvent is evaporated, and the residue triturated with EtOAc, and the insoluble material filtered to give 270 mg of the product 195. 1H NMR (CDCl3) δ 8.60 (s, 1 H), 7.40-7.10 (m, 3 H), 5.15-4.90 (m, 2 H), 4.30-4.10 (m, 2 H), 2.70-2.55 (m, 1 H), 2.20-2.05 (m, 1 H), 1.85-1.10 (m, 15 H); MS: m/z 366 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH3:11].C(O)C.O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>C(OC(=O)C)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH3:11])[NH2:8]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-bromo-4-nitrotoluene (50 g, 0.231 mol in ethylacetate (330 mL) and Ethanol (150 mL) was added Tin(II)chloride dihydrate (208 g, 0.924 mol) portionwise. The reaction mixture was stirred at room temperature overnight. The solution was then treated with potassium carbonate until pH=7 and filtered over celite. The filtrate was washed with water, aqueous NaHCO3, water and brine, dried (Mg2SO4), filtered and evaporated to give 42.71 g (100%) of 3-bromo-4-methylaniline. 1H NMR (300 MHz; CDCl3): 2.27 (s, 3 H), 3.57 (br s, 2 H), 6.54 (dd, J=2.7 Hz and 8.1 Hz, 1 H), 6.90 (d, J=2.1 Hz, 1 H), 6.98 (d, J=8.1 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:11]([OH:13])=[O:12])=[C:5]([CH3:7])[N:6]=1.IC1NC(C2(C)[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=NC=1C.I[C:40]1NC(C)=NC=1C>>[C:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][C:1]([C:2]2[NH:3][C:4]([C:8]3[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=3[CH3:17])[C:11]([OH:13])=[O:12])=[C:5]([CH3:7])[N:6]=2)([CH3:40])[CH2:25][CH2:26]1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Reactant: Cc1nc(C2(C)CCN(C(=O)OC(C)(C)C)CC2)[nH]c1I
Reactant: Cc1nc(C)c(I)[nH]1
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2(C)CCN(C(=O)OC(C)(C)C)CC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except tert-butyl 4-(5-iodo-4-methyl-1H-imidazol-2-yl)-4-methylpiperidine-1-carboxylate (compound 185.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([O:46][CH3:47])[C:32]=1[OH:48]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH2:21][CH2:22]2)[CH:34]=[C:33]([O:46][CH3:47])[C:32]=1[OH:48]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: O=C(c1cnc2ccc(Br)cc2c1N1CCC(CN2CCOCC2)CC1)C1CC1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC(CN5CCOCC5)CC4)c3c2)cc(Cl)c1O
Yield: 57.4 %

Procedure:
Following general procedure D, {6-bromo-4-[4-(morpholinomethyl)piperidin-1-yl]quinolin-3-yl}(cyclopropyl)methanone (30 mg, 0.065 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (42 mg, 0.150 mmol) to afford the desired product (20 mg, 57%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.73 (s, 1H), 8.33 (d, J=1.7 Hz, 1H), 8.07-7.97 (m, 2H), 7.33 (d, J=2.1 Hz, 1H), 7.26 (d, J=2.1 Hz, 1H), 4.00 (s, 3H), 3.75-3.68 (m, 4H), 3.55 (d, J=12.7 Hz, 2H), 3.25-3.15 (m, 2H), 2.61-2.41 (m, 5H), 2.36 (d, J=6.9 Hz, 2H), 2.07-1.90 (m, 3H), 1.68-1.54 (m, 2H), 1.37-1.27 (m, 2H), 1.26-1.20 (m, 2H); ESI MS m/z 536 [C30H34ClN3O4+H]+; HPLC>99% (AUC), tR=10.57 min.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[O:29][CH3:30])[CH:12]=[CH:13][C:14]=2/C=C/C(OCC)=O)=[C:6]([CH3:31])[CH:5]=1)(=[O:3])[NH2:2].[H][H].C1C[O:37][CH2:36]C1>[Ni]>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:11]2[CH:12]=[CH:13][C:14]([CH2:36][OH:37])=[C:10]2[C:7]2[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[CH:5][C:6]=2[CH3:31])=[C:23]([O:29][CH3:30])[CH:24]=1
Reactant: [H][H]
Reactant: C1CCOC1
Reactant: CCOC(=O)/C=C/c1ccn(-c2ccc(Cl)cc2OC)c1-c1ccc(C(N)=O)cc1C
Agent: [Ni]
Product: COc1cc(Cl)ccc1-n1ccc(CO)c1-c1ccc(C(N)=O)cc1C

Procedure:
To a solution of (E)-ethyl 3-(2-(4-carbamoyl-2-methylphenyl)-1-(4-chloro-2-methoxyphenyl)-1H-pyrrol-3-yl)acrylate (610 mg, 1.4 mmol) in THF (10 mL) was added Raney Ni (100 mg), and the reaction mixture was hydrogenated at room temperature under 1 atm of hydrogen for two hours. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound (610 mg), which was used in the next step without further purification.