Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[C:10]([CH3:21])=[N:11][O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[OH:8])[CH:2]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:17]3[CH:16]=[CH:15][C:14]([C:13]4[O:12][N:11]=[C:10]([CH3:21])[C:9]=4[CH:7]([C:3]4[CH:2]=[C:1]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:6]=[CH:5][CH:4]=4)[OH:8])=[CH:19][CH:18]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cccc(-c2ccccc2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cccc(-c5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using biphenyl-3-yl-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[C:3]#[N:4].F[B-](F)(F)F.[CH2:19]([O:21][C:22](=[O:27])[C:23](SC)=[NH2+:24])[CH3:20]>O1CCOCC1>[NH2:4][C:3]1[NH:24][C:23]([C:22]([O:21][CH2:19][CH3:20])=[O:27])=[N:1][C:2]=1[CH2:5][CH2:6][C:7]([F:12])([F:13])[C:8]([F:10])([F:9])[F:11]
Reactant: N#CC(N)CCC(F)(F)C(F)(F)F
Reactant: CCOC(=O)C(=[NH2+])SC
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(CCC(F)(F)C(F)(F)F)c(N)[nH]1

Procedure:
A solution of 2-amino-5,5,6,6,6-pentafluorohexanenitrile (0.5722 g, 2.83 mmol) and 2-ethoxy-1-(methylsulfanyl)-2-oxoethaniminium tetrafluoroborate (0.808 g, 3.45 mmol) in dry 1,4-dioxane (5.2 mL) was stirred at 25° C. under N2 for 6 days. The solution was concentrated in vacuo. The resulting residue was purified by silica gel chromatography using DCM/MeOH gradient to afford the desired product, as an orange oil. 1H NMR (500 MHz, CHCl3-d): δ 4.36 (q, J=7.1 Hz, 2H); 2.85 (br s, 2H); 2.41-2.16 (m, 3H); 2.11-1.94 (m, 1H); 1.35 (t, J=7.1 Hz, 3H). m/z 302.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:5][N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[CH3:42][N:43]([CH3:48])[C:44](=[O:47])[CH2:45]Cl>>[CH3:42][N:43]([CH3:48])[C:44](=[O:47])[CH2:45][N:20]1[CH2:19][CH2:18][N:17]([C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:6]4[C:2]([CH3:1])=[N:3][N:4]([C:23]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:5]=4)[CH:8]=3)[N:13]=[CH:12][CH:11]=2)[CH2:22][CH2:21]1
Reactant: CN(C)C(=O)CCl
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCNCC3)c2c1
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(CC(=O)N(C)C)CC3)c2c1
Yield: 90.6 %

Procedure:
80 mg 6-(3-methyl-1-trityl-1H-4-pyrazolyl)-4-piperazin-1-yl-quinoline obtained in Example 187 and 27 mg N,N-dimethyl-2-chloroacetamide were reacted in the same manner as in Example 190, to give 84 mg of the title compound as a pale yellow amorphous.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([OH:28])=[O:27]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:33]5[CH:32]=[CH:31][CH:30]=[C:29]([C:26]([OH:28])=[O:27])[CH:34]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4cccc(C(=O)O)c4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 3-carboxyphenyl boronic acid. Mass spectrum (ESI) 436.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][C:23]1[CH:28]=[CH:27][C:26](OB(O)O)=[CH:25][CH:24]=1)[CH2:20][CH3:21].ClCCl>C(N(CC)CC)C>[CH2:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:25][CH:24]=1)[CH2:20][CH3:21]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCCOc1ccc(OB(O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Reaction time: 20 h
Yield: 51.7 %

Procedure:
To a mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 4-propoxyphenylboric acid (536 mg), cupric acetate (271 mg), MS (molecular sieves) 4A (1.0 g) and dichloromethane (15 ml) was added at room temperature triethylamine (1.04 ml), and the resulting mixture was stirred for 20 hours. The reaction mixture was filtered to remove an insoluble material and the filtrate was concentrated under reduced pressure. The residue was subjected to separation and purification using column chromatography (ethyl acetate:hexane 1:2) to obtain methyl 7-(4-propoxyphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.31 g) as a light yellow, oily substance.
Reaction SMILES: ClCl.[Pb]([S:7][C:8]#[N:9])SC#N.[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[CH:14][CH:13]=1>C(O)(=O)C>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][C:23]([S:7][C:8]#[N:9])=[CH:24][C:19]=1[CH2:18][C:15]1[CH:16]=[N:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1
Reactant: N#CS[Pb]SC#N
Reactant: COc1ccc(Cc2ccccc2OC)cn1
Agent: ClCl
Solvent: CC(=O)O
Product: COc1ccc(Cc2cc(SC#N)ccc2OC)cn1
Yield: 123.5 %

Procedure:
To dry acetic acid (250 ml, dried by refluxing with 5% acetic anhydride for 4.5 hours) was added dry chlorine (16.00 g). Lead thiocyanate (36.48 g) was added in portions with rapid stirring then after 40 minutes 2-(6-methoxy-3-pyridylmethyl)-anisole (45.85 g) in dry acetic acid (175 ml) was added slowly from a dropping funnel. The mixture was stirred at room temperature for 20 hours, filtered, poured into water (approximately 2 litres) and extracted with chloroform. The combined chloroform extracts were washed with water, 2N sodium hydroxide, water, then dried with anhydrous magnesium sulphate and evaporated to dryness to give an orange gum which was crystallised from chloroform/petroleum spirit (60°-80°) to give 4-methoxy-3-(6-methoxy-3-pyridylmethyl)phenylthiocyanate as a yellow solid (39.89 g, 55%), m.p. 56°-58°.
Reaction SMILES: [CH2:1]([C:3]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:4]=1[C:5]([C:7](=[CH:13]OCC)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6])[CH3:2].[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH2:1]([C:3]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:4]=1[C:5]([C:7](=[CH:13][NH:28][CH:25]1[CH2:27][CH2:26]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6])[CH3:2]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(F)c(F)c(F)c1CC
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(F)c(F)c(F)c1CC

Procedure:
Employing ethyl 2-(2-ethyl-3,4,5,6-tetrafluorobenzoyl)-3-ethoxyacrylate and cyclopropylamine, the procedure of Reference Example 21 is repeated to give ethyl 2-(2-ethyl-3,4,5,6-tetrafluorobenzoyl)-3-cyclopropylaminoacrylate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[O:14]1CCOCC1.O>>[C:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH:1]=[O:14])=[N:3][CH:4]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccc(-c2ccccc2)cn1
Reactant: C1COCCO1
Solvent: O
Product: O=Cc1ccc(-c2ccccc2)cn1
Temperature: 110 °C
Yield: 14 %

Procedure:
To a solution of 2-methyl-5-phenyl-pyridine (800 mg, 4.73 mmol) (Koyama, J. et al. Heterocycles, 1994, 38, 1595-1600) in mixture of dioxane/water (20 mL:2 mL) was added SeO2 (577 mg, 5.20 mmol). The reaction mixture was heated to 110° C. overnight. Then the reaction mixture was cooled and concentrated in vacuo. Purification by flash column chromatography on silica gel using 1:4 hexanes/EtOAc afforded 5-phenyl-pyridine-2-carbaldehyde as a pale yellow solid (124 mg, 14%). 1H NMR (CDCl3) δ 7.49-7.52 (m, 3H), 7.63-7.66 (m, 2H), 8.05 (s, 2H), 9.02 (d, 1H, J=3.0 Hz), 10.12 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([OH:15])(=O)=[O:13])=[CH:7]2.CN(C=O)C.S(Cl)([Cl:23])=O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([Cl:23])(=[O:15])=[O:13])=[CH:7]2
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1ccc2c(Br)cccc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc2c(Br)cccc2c1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a round bottom flask was added 5-bromonaphthalene-2-sulfonic acid (5.00 g, 17.41 mmol), followed by DMF (17.41 mL) to generate a deep green heterogeneous solution. Thionyl chloride (2.54 mL, 34.8 mmol) was added dropwise using a syringe at rt, and the solution turned orange and heat was evolved. The solution became homogeneous. The solution was maintained at rt for 18 h. The resulting orange solution was poured into a separatory funnel containing ice and diluted with DCM (200 mL). When the ice melted, the mixture was shaken and then the resulting layers were separated. The aqueous layer was extracted with DCM (1×50 mL). The combined organic layers were washed with water (3×200 mL), then dried over Na2SO4 and concentrated to provide 5-bromonaphthalene-2-sulfonyl chloride (5.00 g, 16.36 mmol) as a brown oil, which was used immediately without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH:32]2[CH2:34][CH:33]2[C:35]([O:37]CC)=[O:36])=[CH:4][N:3]=1.[OH-].[Na+].Cl>CO>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH:32]2[CH2:34][CH:33]2[C:35]([OH:37])=[O:36])=[CH:4][N:3]=1
Reactant: CCOC(=O)C1CC1c1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2csc3c(C4CC4C(=O)O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Yield: 14.8 %

Procedure:
Ethyl 2-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridin-7-yl]cyclopropanecarboxylate (433 mg, 0.8018 mmol) in methanol (2 mL) and 2M sodium hydroxide (1.604 mL, 3.207 mmol) was stirred for 23 hours at 50° C., cooled to room temperature, and acidified to a pH of 4 with 1M hydrochloric acid. Solids were filtered off and washed with water. The material was purified by HPLC preparative to furnish the title compound as a white solid (61 mg 0.119 mmol): LCMS (Conditions a): MH+=513 Rt =2.22 minutes; 1H NMR (DMSO-d6, 400 MHz) 9.51 (1H), 7.99 (1H), 7.71 (2H), 7.57 (2H), 7.34 (2H), 7.19 (1H), 7.15 (1H), 7.07 (1H), 5.46 (1H), 4.04 (3H), 3.91 (3H), 2.39 (1H), 1.73 (1H), 1.46 (1H), 1.39
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[OH:11][CH2:12][C:13](CO)(CO)[CH2:14]O>C1(C)C=CC=CC=1>[CH2:1]([Sn:5]1([CH2:6][CH2:7][CH2:8][CH3:9])[O:11][CH2:12][CH2:13][CH2:14][O:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: OCC(CO)(CO)CO
Reactant: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCCC[Sn]1(CCCC)OCCCO1
Temperature: 25 °C
Reaction time: 26.5 h
Yield: 87.5 %

Procedure:
49.78 g (0.2 mol) of dibutyltin oxide and 13.615 g (0.1 mol) of pentaerythritol were introduced into a 1000 ml reaction vessel equipped with a Dean-Stark device, and the atmosphere in the reaction vessel was replaced by argon. 500 ml of toluene was added, and the mixture was dehydrated by azeotropic distillation at 130° C. and stirred for 26.5 hours during which it became an uniform solution. After left and cooled to room temperature, the precipitated white solids were filtered. The white solids were heated and dissolved in 300 ml of toluene, and cooled gradually to room temperature, and the precipitated white solids were filtered. The resulting white solids were dried at 60° C. for 5 hours in vaccuo to give 4,4′-spirobi[1,1-dibutylstanna-2,6-dioxacyclohexane, 52.3 g (87.5% yield).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][C:10]([CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])([NH:12]CC3C=CC=CC=3)[CH2:9]2)C=CC=CC=1.[ClH:31].O1CCOCC1>CO.[OH-].[Pd+2].[OH-]>[ClH:31].[CH3:23][CH:22]([NH:21][CH2:20][C:10]1([NH2:12])[CH2:11][NH:8][CH2:9]1)[CH3:24]
Reactant: CC(C)NCC1(NCc2ccccc2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)NCC1(N)CNC1
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of the 1-(diphenylmethyl)-3-{[(1-methylethyl)amino]methyl}-N-(phenylmethyl)azetidin-3-amine (0.35 g, 0.88 mmol) in methanol was added a solution of hydrogen chloride in dioxane (4 molar solution, 0.96 mL, 4.40 mmol) and the resulting mixture was concentrated to give a white solid which was taken back into methanol. To this solution were added palladium hydroxide (20% on carbon, 0.50 g, 0.19 mmol) and the resulting mixture shaken at 50 psi in a Parr apparatus for 3 h. The reaction mixture was filtered and concentrated to give a solid, which was washed with ether and dried in vacuo to give 3-{[(1-methylethyl)amino]methyl}azetidin-3-amine hydrochloride as a white solid (0.18 g, 81% yield). MS (EI) for C7H17N3: 144 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C@:17]3([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30]([OH:32])=O)[NH:19][C@H:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]1[CH:70]=[C:69]([O:71][CH2:72][CH2:73][S:74][CH3:75])[CH:68]=[CH:67][C:66]=1[NH2:76]>>[CH3:63][O:64][C:65]1[CH:70]=[C:69]([O:71][CH2:72][CH2:73][S:74][CH3:75])[CH:68]=[CH:67][C:66]=1[NH:76][C:30]([C@@H:20]1[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C@:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[C@H:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:32]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc(OCCSC)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OCCSC)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 136 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.45 g, 3.5 mmol), diphenylphosphinic chloride (0.33 g, 1.4 mmol), then reacted with 2-methoxy-4-(2-methylsulfanyl-ethoxy)-phenylamine prepared in Example 168 (0.2 g, 0.9 mmol) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [2-methoxy-4-(2-methylsulfanyl-ethoxy)-phenyl]-amide as a off white solid (Yield 0.2 g, 44%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([CH3:25])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[N:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([CH3:25])[S:22][C:12]=3[N:13]=2)=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: Cc1cc2c(NCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-4-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-benzylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(OCC)=O.NC[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[NH:22]1[CH:21]=[C:20]([CH2:19][CH2:1][N:6]2[C:7](=[O:16])[C:8]3[C:9](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:11])[N:24]=[CH:23]1
Reactant: NCCc1c[nH]cn1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]cn1

Procedure:
N-Carbethoxy phthalimide (2.45 g, 11 mmol) is added over 10 minutes to a vigorously stirred solution of histamine (1.13 g, 1.0 mmol) and Na2CO3 (1.19 g, 1.1 mmol) in water (22 ml). After 1 h the white suspension is removed by filtration, washed with ethanol and dried to afford the titled compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:6]=2[C:5](=[O:31])[NH:4][C:3]1=[O:32].CS(O[CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]2[N:9]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:21])([F:22])[F:20])[CH:13]=3)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:6]=2[C:5](=[O:31])[N:4]([CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])[C:3]1=[O:32]
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2COCC[Si](C)(C)C
Reactant: CS(=O)(=O)OCCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCC(F)(F)F)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2COCC[Si](C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of 3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (500 mg, 1.06 mmol, intermediate 12, step 2) in DMF (6 mL) was added 3,3,3-trifluoropropyl methanesulfonate (305 mg, 1.59 mmol) followed by potassium carbonate (439 mg, 3.17 mmol). The reaction was stirred at 60° C. overnight. The mixture was diluted with ethyl acetate and extracted with brine. The organic phase was dried and concentrated to give 3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (510 mg, 84.6% yield) as yellow syrup. LCMS retention time 2.275 min; LCMS MH+ 569.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=2[Cl:8])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Yield: 67.9 %

Procedure:
To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (460 mg, 1.2 mmol) and 4-chlorophenylboronic acid (225 mg, 1.44 mmol) in toluene (10 mL) was added Pd(0) (40 mg) and Na2CO3 (1.2 mL of a 2M solution), and the mixture was heated at reflux for 1.5 hours. The solvent was removed under vacuum, and the residue was purified by chromotography on a silica gel column, eluting with hexane:ether 100:10-100:30 to afford of the title compound (345 mg, 68% yield). MS (DCI/NH3) m/z 423 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.45 (s, 9H), 1.89 (m, 2H), 2.03 (m, 2H), 3.37 (m, 2H), 4.00 (m, 1H), 4.15 (m, 2H), 7.42 (m, 6H), 8.10 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[C:17](Cl)[N:16]=2)=[CH:11][C:10]=1[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH2:1]([N:8]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[C:17]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:16]=2)=[CH:11][C:10]=1[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: FC(F)(F)c1cc(-c2cc3ncccc3c(Cl)n2)ccc1N(Cc1ccccc1)Cc1ccccc1
Product: FC(F)(F)c1cc(-c2cc3ncccc3c(N3CCOCC3)n2)ccc1N(Cc1ccccc1)Cc1ccccc1
Yield: 26 %

Procedure:
A solution of dibenzyl-[4-(5-chloro-[1,6]naphthyridin-7-yl)-2-trifluoromethyl-phenyl]-amine, 3, (100 mg, 0.20 mmol, 1 eq) in morpholine (1.25 mL, 14 mmol, 70 eq) was heated up at 100° C. overnight under Ar(g). Once cooled down, the solution was partitioned and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (1:3-0:1) to yield the product as a pale yellow solid (29.1 mg, 26%).
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[Cl:37][C:38]1[CH:46]=[C:45]2[C:41]([CH2:42][CH2:43][NH:44]2)=[CH:40][CH:39]=1>ClCCCl>[Cl:37][C:38]1[CH:46]=[C:45]2[C:41]([CH2:42][CH2:43][N:44]2[C:9]2[C:4]3[CH:3]=[C:2]([CH3:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)=[CH:40][CH:39]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: Cc1cc2c(=O)[nH]cnc2cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc2c(N3CCc4ccc(Cl)cc43)ncnc2cn1
Temperature: 60 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
6Methyl-pyrido[3,4-d]pyrimid-4one (200 mg, 1.24 mmol), polymer-supported triphenylphosphine (2.06 g of 3.0 mmol Pig resin, 6.20 mmol) and anhydrous carbon tetrachloride (1.20 mL, 12.40 mmol) were combined in 1,2-dichloroethane (6 mL). The mixture was heated to 60° C. under an atmosphere of dry N2(g) for 18 hours. 6-Chloroindoline (1.1 eq.) was added and heating was continued at 60° C. for another 18 hours. The triphenyphosphine-bearing resin was filtered off and washed several times with chloroform. The filtrate and washings were concentrated in vacuo and preparative reversed-phase (C18) chromatography utilizing a gradient of 15% to 70% MeCN/pH4.5, 50 mM NH4OAc followed by lyophilization of the appropriate fractions afforded the title product (30%) as its free-base: MP: 232-234° C.; LC-MS: 297 (MH+); anal. RP-HPLC: 4.33 minutes.
Reaction SMILES: [CH:1]([Si:4]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:5][CH2:6][C:7]1[S:11][N:10]=[N:9][C:8]=1[C:12]([O:14]C)=O)([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26].C(Cl)Cl.C[Al](C)C>CCCCCC>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:12]([C:8]2[N:9]=[N:10][S:11][C:7]=2[CH2:6][O:5][Si:4]([CH:16]([CH3:17])[CH3:18])([CH:19]([CH3:20])[CH3:21])[CH:1]([CH3:2])[CH3:3])=[O:14])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: COC(=O)c1nnsc1CO[Si](C(C)C)(C(C)C)C(C)C
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)[Si](OCc1snnc1C(=O)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
To a cooled solution (0° C.) of methyl 5-[(triisopropylsilyl)oxy]methyl-1,2,3-thiadiazole-4-carboxylate (2.2 g, 0.0066 mol) and 3-chloro-4-fluoroaniline (1.5 g, 0.010 mol) in DCM (20 mL, 0.4 mol) was added 2.0 M of trimethylaluminum in hexane (12 mL) under nitrogen and stirred for 15 minutes. The volatiles were removed in vacuo and the crude was purified by flash chromatography to give the desired product (2.3 g, 78%). MF=C19H27ClFN3O2SSi; LCMS calculated for C19H28ClFN3O2SSi (M+H)+: m/z=444.1.