Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([OH:21])[CH2:18][CH2:19][CH3:20].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:7]([O:21][CH2:17][CH2:18][CH2:19][CH3:20])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: CCCCO
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCOc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, butanol and DBU in dioxane. ES-MS m/e (%): 314 (M{81Br}+H+, 100), 312 (M{79Br}+H+, 98), 258 ([M{81Br}+H-EtCH═CH2]+, 92), 256 ([M{8Br}+H-EtCH ═CH2]+, 90).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[NH:5][C:4](=[O:13])[C:3]=1[C:14]#[N:15].[N:16]1([C:22]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[N:7][CH:8]=1)[NH:5][C:4](=[O:13])[C:3]([C:14]#[N:15])=[C:2]2[N:19]1[CH2:20][CH2:21][N:16]([C:22]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:17][CH2:18]1
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: N#Cc1c(Cl)c2cc(F)cnc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2[nH]c1=O
Yield: 79 %

Procedure:
This compound was prepared from 4-chloro-6-fluoro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (96) and piperazin-1-yl-thiophene-2-yl-methanone according to general procedure E to yield 4.85 g (79%) of 6-fluoro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (98) as yellow solids. MP 244° C.; 1H-NMR (DMSO-d6): δ 3.72 (m, 4H), 3.91 (m, 4H), 7.16 (dd, J=3.6, 4.8 Hz, 1H), 7.49 (d, J=3.6 Hz, 1H), 7.80 (d, J=5.2 Hz, 1H), 8.05 (dd, J=2.8, 7.2 Hz, 1H), 8.70 (d, J=2.8 Hz, 1H); EIMS: 384 (M+1).
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=O)[C:7]2=[O:15].Cl.[NH2:17][NH:18][C:19]([NH2:21])=[S:20]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=[N:17][NH:18][C:19]([NH2:21])=[S:20])[C:7]2=[O:15]
Reactant: COc1ccc2c(=O)c(=O)c(=O)c2c1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Product: COc1ccc2c(=O)c(=NNC(N)=S)c(=O)c2c1

Procedure:
5-methoxyindan-1,2,3-trione, monohydrate, thiosemicarbazide hydrochloride
Reaction SMILES: [CH3:1][N:2]1[CH2:5][C:4]2([CH2:14][C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](/[CH:16]=[CH:17]/[C:18](O)=[O:19])[CH:11]=3)[O:6]2)[CH2:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:35][O:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][C:4]2([CH2:14][C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](/[CH:16]=[CH:17]/[C:18]([NH:35][O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][O:38]4)=[O:19])[CH:11]=3)[O:6]2)[CH2:5]1
Reactant: NOC1CCCCO1
Reactant: CN1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Yield: 70.8 %

Procedure:
A suspension of (E)-3-[1′-methyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (400 mg, 1.29 mmol) in DCM (16 ml) was treated with TEA (0.30 ml, 2.2 mmol) and then with EDC (420 mg, 2.20 mmol), HOBt (297 mg, 2.20 mmol) and NH2OTHP (204 mg, 1.75 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-methyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (340 mg) as a light yellow solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH:31]1([NH2:35])[CH2:34][CH2:33][CH2:32]1>>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:35][CH:31]3[CH2:34][CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: NC1CCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Product: Fc1cc2c(c(-c3c(Cl)cccc3Cl)c1)OC(CNC1CCC1)C2

Procedure:
The title compound was prepared (0.074 g, 61%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.30 mmol) and cyclobutylamine (0.21 g, 3.0 mmol). mp 128-130° C.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1>>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: CC(=O)Nc1ccc(N)cc1
Product: CC(=O)Nc1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Yield: 13.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and N-(4-Amino-phenyl)-acetamide (38 mg, 0.33 mmol) to provide 234 (10 mg, 17% yield) as a brown solid. LC-MS (M+H=345, obsd.=345).
Reaction SMILES: [C:1]1([C:7](=[O:17])[CH2:8][CH:9](O)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:18]>>[C:1]1([C:7](=[O:17])[CH2:8][CH:9]([Cl:18])[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(O)C1CCCCC1)c1ccccc1
Reactant: Cl
Product: O=C(CC(Cl)C1CCCCC1)c1ccccc1
Yield: 96 %

Procedure:
The reaction and post treatment were carried out in the same manner as in Example 10 except that 1-phenyl-3-hydroxy-3-cyclohexylpropan-1-one obtained by the same production process as in Preparation Example 1, was used as the starting material, and hydrochloric acid (180 g) was changed to hydrogen chloride gas (20° C., 12,300 ml, 511 mmol), and the reaction was carried out at −20° C., whereby the desired 1-phenyl-3-chloro-3-cyclohexylpropan-1-one (97.1 g, 407 mmol) was obtained in a yield of 96%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:21]1([S:27]([Cl:30])(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>>[ClH:30].[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:18])[F:19])[CH:15]=3)[N:10]([S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CC=C(c2c[nH]c3ccc(C(F)(F)F)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc(C(F)(F)F)cc23)CC1

Procedure:
(14.9 mg, 46%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethyl-1H-indole (Example 4i, 20 mg, 0.071 mmol) and phenylsulfonyl chloride (18.9 mg, 0.107 mmol). HRMS-FAB+ for C21H19N2O2SF3.HCl, calculated MH+ (--HCl): 421.11975; found: 421.11923.
Reaction SMILES: [N:1]1[C:6]([NH2:7])=[CH:5][C:4]([NH2:8])=[N:3][CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>O1CCOCC1>[NH2:8][C:4]1[N:3]=[CH:2][N:1]=[C:6]([NH:7][C:9](=[O:11])[CH3:10])[CH:5]=1
Reactant: Nc1cc(N)ncn1
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(N)ncn1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a stirred suspension of pyrimidine-4,6-diamine (500 mg, 4.55 mmol) in dioxane (20 mL) was added acetic anhydride (465 mg, 4.55 mmol) and the resulting mixture was heated under reflux for 15 hours. The reaction was cooled to room temperature and the resulting precipitate was collected by filtration. The filtercake was dissolved in 1N HCl and the pH of the aqueous phase adjusted to 7 by the addition of 1N NaOH. The resulting white precipitate was collected by filtration and dried to afford the desired product as a white solid (420 mg, 61% yield). LCMS (ESI) m/z: 152.0 [M+H+].
Reaction SMILES: CS(C)=O.[CH3:5][N:6]1[C:11]([NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH3:17])=[CH:10][C:9](=[O:18])[N:8]([CH3:19])[C:7]1=[O:20].[CH3:21][C:22]1[C:27](=[O:28])[C:26]2[C:29]([O:33][CH2:34][CH2:35][CH2:36]Br)=[CH:30][CH:31]=[CH:32][C:25]=2[O:24][CH:23]=1>C(N(CC)CC)C>[CH3:5][N:6]1[C:11]([NH:12][CH2:13][CH2:14][N:15]([CH2:16][CH3:17])[CH2:36][CH2:35][CH2:34][O:33][C:29]2[C:26]3[C:27](=[O:28])[C:22]([CH3:21])=[CH:23][O:24][C:25]=3[CH:32]=[CH:31][CH:30]=2)=[CH:10][C:9](=[O:18])[N:8]([CH3:19])[C:7]1=[O:20]
Reactant: Cc1coc2cccc(OCCCBr)c2c1=O
Reactant: CCNCCNc1cc(=O)n(C)c(=O)n1C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCN(CCCOc1cccc2occ(C)c(=O)c12)CCNc1cc(=O)n(C)c(=O)n1C
Reaction time: 6 h

Procedure:
To 5 ml of dimethyl sulfoxide were added 0.52 g of the previously obtained N-[1,3-dimethyl-2,4-dioxopyrimidine-6-yl]-N'-ethylethylenediamine (Compound 13), 0.7 g of 3-(3-methyl-4-oxo-4H-1-benzopyran-5-yl)oxypropyl bromide (Compound 2) and 0.5 ml of triethylamine, and reaction was carried out at 100° C. for 6 hours. The resultant reaction solution was cooled, and the formed white crystals were collected by filtration, washed with water, and then dried, thereby obtaining 0.56 g of 1,3-dimethyl-6-(2-[N-ethyl-N-[3-(3-methyl-4-oxo-4H-1-benzopyran-5-yl)oxypropyl]amino]ethylamino)-2,4(1H,3H)-pyrimidinedione (the non-oxalate of Compound 14).
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:29][CH2:30][CH:31]1[O:35][C:34](=[O:36])[NH:33][CH2:32]1>>[ClH:29].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:30][CH:31]4[O:35][C:34](=[O:36])[NH:33][CH2:32]4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: O=C1NCC(CCl)O1
Agent: Cl
Product: O=C1NCC(CN2CN(c3ccccc3)C3(CCN(C4CCCCCCCCC4)CC3)C2=O)O1

Procedure:
The title compound, white solid, m. p. 174° C. and MS: m/e=469.3 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 5-chloromethyl-2-oxazolidinone.
Reaction SMILES: [CH:1]([S:5][C:6]1[S:7][CH:8]=[C:9]([O:11][S:12]([CH3:15])(=[O:14])=[O:13])[N:10]=1)([CH2:3][CH3:4])[CH3:2].[OH:16]O.O.[OH-].[Na+]>C(O)(=O)C>[CH:1]([S:5]([C:6]1[S:7][CH:8]=[C:9]([O:11][S:12]([CH3:15])(=[O:13])=[O:14])[N:10]=1)=[O:16])([CH2:3][CH3:4])[CH3:2]
Reactant: OO
Reactant: CCC(C)Sc1nc(OS(C)(=O)=O)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCC(C)S(=O)c1nc(OS(C)(=O)=O)cs1
Yield: 49.7 %

Procedure:
4.0 g of 2-sec-butylthio-4-methylsulfonyloxy-1,3-thiazole was dissolved in 15 ml of acetic acid, and 2.2 ml of 35% aqueous hydrogen peroxide was added to the solution at room temperature, followed by reaction at 30° to 40° C. for 4 hours. The reaction mixture was poured into chilled water, neutralized by 5% aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate and concentrated to obtain an oil, which was purified by silica-gel column chromatography to 2.1 g of the objective compound as a pale yellow oil (yield: 49.7%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]2[N:17]=[C:16]([O:18][C@H:19]3[CH2:23][CH2:22][O:21][CH2:20]3)[C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][N:34]([CH3:49])[CH2:35][CH2:36][NH:37][C:38]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)=[O:39]>CN(C=O)C.O>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]2[N:17]=[C:16]([O:18][C@H:19]3[CH2:23][CH2:22][O:21][CH2:20]3)[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:43]4[CH:44]=[CH:45][C:40]([C:38]([NH:37][CH2:36][CH2:35][N:34]([CH3:33])[CH3:49])=[O:39])=[CH:41][CH:42]=4)[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)CCNC(=O)c1ccc(B(O)O)cc1
Reactant: Fc1ccc(CNc2nc(O[C@H]3CCOC3)c3cc(Br)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCNC(=O)c1ccc(-c2ccc3nc(NCc4ccc(F)cc4)nc(O[C@H]4CCOC4)c3c2)cc1
Yield: 64.5 %

Procedure:
(S)—N-(4-fluorobenzyl)-6-bromo-4-(tetrahydrofuran-3-yloxy)quinazolin-2-amine (50 mg, 0.12 mmol), potassium carbonate (33 mg, 0.24 mmol), tetrakis(triphenyl-phosphine)palladium (8 mg, 0.007 mmol) and 4-((2-(dimethylamino)ethyl)-carbamoyl)phenylboronic acid (36 mg, 0.132 mmol) in DMF (1.0 mL) and water (0.3 mL) was heated to 150° C. for 10 minutes under microwave irradiation. Solvents were concentrated in vacuo and the residue was purified by RP HPLC, using a C18 column with a gradient of 0.1% H2O, 0.1% TFA-acetonitrile, to provide the desired product (41 mg) which was characterized by its mass spectrum as follows: MS (m/z): 530 ([M+H]+, 100); HPLC Rt=1.26 minutes (Method B).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](O)=[N:5][C:6]([C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)=[N:7]2.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1)=[N:5][C:6]([C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)=[N:7]2
Reactant: Oc1nc(-c2cncnc2)nc2cccc(Br)c12
Reactant: NCc1ccccn1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Brc1cccc2nc(-c3cncnc3)nc(NCc3ccccn3)c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.6 %

Procedure:
To a stirred suspension of 5-bromo-2-(pyrimidin-5-yl)quinazolin-4-ol (2.0 g, 6.5 mmol) in DMF (20 mL) was added diisopropylethyl amine (3.4 ml, 19 mmol) followed by PyBroP (3.7 g, 7.9 mmol). After 5 min stirring at room temperature, 2-aminomethylpyridine (1.0 mL, 9.8 mmol) was added to the reaction. Upon completion of addition, the reaction mixture was warmed to 80° C. where it stirred for 2 h (during which time reaction became a clear solution). At the conclusion of this period, the reaction mixture was quenched by the addition of cold water and then extracted into 50% ethyl acetate and hexane mixture (200 mL). The organic extracts were dried, concentrated, purified by column chromatography using ethyl acetate and hexanes as eluent to yield the crude produce. The crude product was further purified by trituration with ethyl acetate and hexane to yield 5-bromo-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (0.5 g, 20% yield). 1H NMR (400 MHz, CDCl3, δ): 5.07 (d, J=4.4 Hz, 2H); 7.26 (m, 1H); 7.41 (d, J=7.6 Hz, 1H); 7.53 (t, J=8 Hz, 1H); 7.71-7.73 (m, 2H); 7.86 (dd, J=0.8 Hz, 8.4 Hz, 1H); 8.65 (d, J=4 Hz, 1H); 9.30 (s, 1H); 9.38 (br s, 1H); 9.75 (s, 2H). ES-MS: [M++1]=393 and [M++3]=395.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][N:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O)[CH3:37]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:29]=[C:30]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[CH2:38][N:36]([CH3:37])[CH3:35])[CH:31]=[CH:32][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CN(C)Cc1ccccc1B(O)O
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)c4)cc3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5CN(C)C)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(3-bromo-phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-(N,N-dimethylaminomethyl)-phenylboronic acid. (1,1′-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14](B(O)O)[CH:13]=1>>[Cl:11][C:8]1[N:9]=[CH:10][C:5]2[S:4][CH:3]=[C:2]([C:14]3[CH:13]=[N:12][C:21]4[C:16]([CH:15]=3)=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:6]=2[N:7]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: Clc1ncc2scc(Br)c2n1
Product: Clc1ncc2scc(-c3cnc4ccccc4c3)c2n1
Yield: 58 %

Procedure:
2-Chloro-7-(quinolin-3-yl)thieno[3,2-d]pyrimidine (140 mg, 58% yield) was prepared in the same manner as Step 6 of Example 1 using 7-bromo-2-chlorothieno[3,2-d]pyrimidine (200 mg, 0.81 mmol) and quinolin-3-ylboronic acid (140 mg, 0.81 mmol).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[C:16]([O:28][CH3:29])=[CH:17][C:18]([C:26]#[N:27])=[C:19]([N:21]=[CH:22]N(C)C)[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:30][C:31]1[CH:35]=[C:34]([CH2:36][C:37]([OH:39])=[O:38])[NH:33][N:32]=1>C(O)(=O)C>[C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]2[C:18]([C:26]([NH:30][C:31]3[CH:35]=[C:34]([CH2:36][C:37]([OH:39])=[O:38])[NH:33][N:32]=3)=[N:27][CH:22]=[N:21]2)=[CH:17][C:16]=1[O:28][CH3:29])([CH3:2])([CH3:4])[CH3:3]
Reactant: Nc1cc(CC(=O)O)[nH]n1
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OC[C@H]1CCCN1CCOC(C)(C)C
Solvent: CC(=O)O
Product: COc1cc2c(Nc3cc(CC(=O)O)[nH]n3)ncnc2cc1OC[C@H]1CCCN1CCOC(C)(C)C
Yield: 49.6 %

Procedure:
N′-(5-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide (300 mg, 0.74 mmol) in acetic acid (0.64 ml) was reacted with (3-amino-1H-pyrazol-5-yl)acetic acid (110 mg, 0.78 mmol) at 120° C. for 20 minutes. The solvent was evaporated, and the residue triturated with dichloromethane to yield {3-[(7-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic acid (183 mg, 47% yield):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]#[C:11][C@@H:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)=[N:6][C:7]=1[O:8][CH3:9].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:10]=[CH:11]\[C@@H:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)=[N:6][C:7]=1[O:8][CH3:9]
Reactant: [H][H]
Reactant: COc1nc(C#C[C@H]2CCC(=O)N2)ccc1Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: COc1nc(/C=C\[C@H]2CCC(=O)N2)ccc1Cl
Yield: 71 %

Procedure:
Lindlar catalyst (50 mg) was added to a solution of (5R)-5-[(5-chloro-6-methoxypyridin-2-yl)ethynyl]pyrrolidin-2-one (232 mg) in methanol (5 mL), and the mixture was stirred at room temperature for eight hours in a hydrogen atmosphere. The reaction solution was filtered through celite, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give the title compound as a colorless oil (166 mg, 71%).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][S:7][CH2:8][C:4]=2[C:3]([NH2:9])=[N:2]1.[C:10]1([CH3:24])[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[CH:18]=[C:19]([C:22]#[N:23])[C:20]#[N:21]>N1C=CC=CC=1>[NH2:23][C:22]1[N:2]2[N:1]=[C:5]3[CH2:6][S:7][CH2:8][C:4]3=[C:3]2[N:9]=[C:18]([C:11]2[C:10]([CH3:24])=[CH:15][C:14]([CH3:16])=[CH:13][C:12]=2[CH3:17])[C:19]=1[C:20]#[N:21]
Reactant: Cc1cc(C)c(C=C(C#N)C#N)c(C)c1
Reactant: Nc1n[nH]c2c1CSC2
Solvent: c1ccncc1
Product: Cc1cc(C)c(-c2nc3c4c(nn3c(N)c2C#N)CSC4)c(C)c1

Procedure:
A solution of 284 mg (2.01 mmol) of 4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-amine (Intermediate 21) and 395 mg (2.01 mmol) of (mesitylmethylene)malononitrile (Intermediate 3) in 5 mL of anhydrous pyridine was stirred at reflux under air overnight (protected from moisture with a calcium sulfate drying tube) and then cooled and concentrated in vacuo. The residue was stirred with 20 mL of methanol and filtered to remove some insoluble material, which was washed with an additional 5 mL of methanol. The combined filtrate and washings were concentrated. Purification of the residue by flash chromatography on silica gel (gradient elution with 5-15% ethyl acetate in hexane) afforded the title compound as a solid. LC-MS 336 (M+1).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][S:6]1(=[O:11])=[O:10].Cl>CC(C)=O>[O:10]=[S:6]1(=[O:11])[CH2:7][CH2:8][CH2:9][N:5]1[CH2:4][CH:3]=[O:2]
Reactant: COC(CN1CCCS1(=O)=O)OC
Agent: Cl
Solvent: CC(C)=O
Product: O=CCN1CCCS1(=O)=O
Temperature: 60 °C

Procedure:
To a solution of 2-[2,2-bis(methyloxy)ethyl]isothiazolidine 1,1-dioxide (1.00 g, 4.77 mmol) in acetone (5 mL) was added hydrochloric acid (600 μL, 1 M aqueous, 0.600 mmol). The reaction mixture was heated at 60° C. for 10 hours, then cooled to room temperature. The excess acetone was removed in vacuo and the resulting residue was partitioned between water and dichloromethane. The organic layer was separated and dried over sodium sulfate. Filtration and concentration, followed by flash chromatography (0 to 5%, methanol in dichloromethane) provided (1,1-dioxido-2-isothiazolidinyl)acetaldehyde as a brown oil. 1H NMR (400 MHz, CDCl3) δ 9.64 (s, 1 H), 3.91 (s, 2 H), 3.39 (m, 2 H), 3.20 (t, J=7.7 Hz, 2 H), 2.44 (m, 2 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[CH2:10][C:3]=12.[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[NH2:20][CH2:19][CH2:18][NH:21][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[CH2:10][C:3]=12
Reactant: NCCN
Reactant: Clc1ccnc2c1CC1(CN3CCC1CC3)O2
Product: NCCNc1ccnc2c1CC1(CN3CCC1CC3)O2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 74 mg (0.295 mmol) of 4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] in 10 mL of ethylenediamine was heated to reflux under a nitrogen atmosphere and stirred for 4 days. Upon cooling to ambient temperature, the solvent was removed in vacuo. The residue was dissolved in 20 mL of saturated aqueous sodium carbonate and extracted with chloroform (3×25 mL). The combined organic extract was dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound as a dark oil, 80 mg (100%): electrospray MS (m/z, relative intensity) 275 ([MH]+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]>CO.[Pd]>[NH2:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([C:3](=[O:4])[C:2]([F:18])([F:1])[F:17])[CH2:6][CH2:7]2
Reactant: O=C(N1CCc2cc([N+](=O)[O-])ccc21)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CCN2C(=O)C(F)(F)F
Reaction time: 8 h
Yield: 110 %

Procedure:
To a suspension of 2,2,2-trifluoro-1-(5-nitroindolin-1-yl)ethanone (7.92 g, 30.4 mmol) in MeOH (100 mL) was added 10% Pd/C (0.648 g, 0.609 mmol) and the slurry was stirred under H2 (1 atm) overnight. The mixture was filtered through a pad of Celite® and the filtrate was concentrated and dried under vacuum to give 7.7 g (crude yield>100%) of 1-(5-aminoindolin-1-yl)-2,2,2-trifluoroethanone as a yellow-brown solid. 1HNMR (400 MHz, CDCl3): δ 8.00 (d, J=8.8 Hz, 1H), 6.59 (s, 1H), 6.57 (d, J=8.4 Hz, 1H), 4.23 (t, J=8.0 Hz, 2H), 3.69 (brs, 2H), 3.16 (t, J=8.2 Hz, 2H); MS (ESI) m/z: 231.0 (M+H+).