Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][CH:8]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[OH:13][CH2:12][CH2:11][CH2:10][S:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH:2]=[O:1]
Reactant: OCCCSc1cccc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cccc(SCCCO)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Manganese dioxide (1.76 g) was added to a solution of 3-(3-(hydroxymethyl)phenylthio)propan-1-ol [Aromatic Intermediate 15, step b] (0.40 g) in DCM (10 mL). The resulting mixture was stirred at room temperature for three days. The suspension was then filtered over Celite, washing the residue well with DCM. The combined filtrate and washings were concentrated under reduced pressure to afford the titled compound as a yellow gum. Yield 0.33 g.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1[CH:14]=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1[CH:14]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([O:24][CH2:25][CH3:26])=[O:23])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCCCCC#Cc1ccoc1C=O
Product: CCCCCCC#Cc1ccoc1C=C(C(=O)OCC)C(=O)OCC

Procedure:
Reaction of 3-(1-octynyl)furan-2-carboxaldehyde (2.04 g, 10 mmole from Example 14) with diethyl malonate (1.98 g, 1.25 eq) as described in Example 3 gave, after chromatography on silica (DCM:Hexane 1:1) 1.96 (57%) of the title compound as an oil, νmax (film) 2930, 2230, 1740, 1725, 1625, 1240, 1210, 1100 cm-1 ; δ(CDCl3) 0.89(3H, distorted t), 1.32(3H, t, J=7.5 Hz), 1.35(3H, t, J=7.5 Hz), 1.40(8H, m), 2.40(2H, t, J=6.5 Hz), 4.28(2H, q, J=7.5 Hz), 4.36(2H, q, J=7.5 Hz), 6.45(1H, d, J=2 Hz), 7.40(1H, d, J=2 Hz), 7.60(1H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12](Cl)=[O:13])=[CH:9][CH:8]=1.[N-:15]=[N+:16]=[N-:17].[Na+].O>CC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([N:15]=[N+:16]=[N-:17])=[O:13])=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cl)c1ccc(-c2ccccn2)s1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NC(=O)c1ccc(-c2ccccn2)s1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 83 %

Procedure:
A solution of 5-(pyrid-2-yl)thiophene-2-carbonyl chloride (254 mg, Reference Example 43) in acetone (3 mL) was treated with a solution of sodium azide (128 mg) in a water and acetone mixture (3.5 mL, 1:6, v/v). After stirring at room temperature for a further 75 minutes the reaction mixture was treated with water (4 mL). The insoluble material was collected and washed with water to give the title compound (217 mg) as a white solid, which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][CH:21]=1
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COc1ccc(O)cc1

Procedure:
EThyl 4-benzyloxyphenoxyacetate (5.8 g.) was hydrogenated in the presence of 0.5 g. of palladium-on-carbon catalyst in 200 ml. of absolute ethanol. There was obtained 4.00 g. of ethyl 4-hydroxyphenoxyacetate, m.p. 124°-125° C. when recrystallized from isopropyl alcohol.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH:21]2[CH2:26][CH:25]([CH2:27][OH:28])[CH2:24][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C1COCC1.O>[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH:21]2[CH2:26][CH:25]([CH2:27][O:28][S:48]([CH3:47])(=[O:50])=[O:49])[CH2:24][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)C1CC(CO)CN(C(=O)OC(C)(C)C)C1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)C1CC(COS(C)(=O)=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-[({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-(hydroxymethyl)piperidine-1-carboxylate (570 mg) and triethylamine (0.25 ml) in THF (10 ml) was added methanesulfonyl chloride (0.1 ml) under ice-cooling, and the mixture was stirred at room temperature 1 hr. Triethylamine (0.25 ml) and methanesulfonyl chloride (0.1 ml) were further added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give the object compound (624 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[NH:9][C:8]2=[N:13][CH:14]=[CH:15][C:7]=12.[CH2:16]([N:23]=[C:24]=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([NH:23][C:24]([NH:12][C:10]1[NH:9][C:8]2=[N:13][CH:14]=[CH:15][C:7]2=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:11]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1nc(-c2ccco2)c2ccnc-2[nH]1
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)Nc1nc(-c2ccco2)c2ccnc-2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.1 %

Procedure:
A solution of 4-(2-furyl)-1H-pyrrolo[2,3-d]pyrimidine-2-amine (192 mg, 0.96 mmol) in THF (3 mL) was treated with benzyl isocyanate (118 μL, 0.96 mmol), stirred at room temperature for 16 h and the resulting solid filtered and washed with EtOAc to give the title compound (61 mg, 19%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].[C:12](Cl)(=O)C(Cl)=O>ClCCl.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH3:12])=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Preparation H11, Step 1: 10 g (0.068 mol) of 3-cyano benzoic acid was taken in 150 ml of dry dichloromethane and cooled to 0° C. Added 50 ml of oxalyl chloride drop wise followed by 5 drops of dry DMF. The reaction mixture was stirred at RT overnight. Dichloromethane was removed and dry methanol (50 ml) was added and stirred at rt for 2 h. Excess methanol was removed and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with 10% of sodium bicarbonate, brine and concentrated to give methyl 3-cyanobenzoate (7 g) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][CH:6]([C:12]([O:14]CC)=[O:13])[C:7]([O:9]CC)=[O:8])=[O:4].[OH-].[Na+:18]>>[OH:1][CH2:2][C:3]([NH:5][CH:6]([C:12]([O-:14])=[O:13])[C:7]([O-:9])=[O:8])=[O:4].[Na+:18].[Na+:18]
Reactant: CCOC(=O)C(NC(=O)CO)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(CO)NC(C(=O)[O-])C(=O)[O-]

Procedure:
Diethyl 2-[(hydroxyacetyl)amino]malonate (0.56 g) is dissolved in 1N aqueous sodium hydroxide (5 ml), and the mixture is reacted at room temperature for 10 hours, and thereafter, the reaction mixture is concentrated under reduced pressure. The residue is washed with methanol to give disodium 2-[(hydroxyacetyl)amino]malonate (0.51 g).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[C:8]([Cl:9])=[CH:7][C:6]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[C:5]([N+:24]([O-])=O)[CH:4]=1.O.NN>C(O)C.[Ni]>[NH2:24][C:5]1[CH:4]=[C:3]([C:2]([F:28])([F:1])[F:27])[C:8]([Cl:9])=[CH:7][C:6]=1[NH:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)c(C(F)(F)F)cc2[N+](=O)[O-])CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)c(C(F)(F)F)cc2N)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-[(4-trifluoromethyl-5-chloro-2-nitrophenyl)amino]-1-piperidinecarboxylate (D61, 6.7 g) was dissolved in ethanol (100 ml) and Raney nickel (50% aqueous suspension, 5 ml) was added at room temperature; the mixture was heated to 50° C. and hydrazine monohydrate (3 ml) was added over 30 min. After 1 h more, the reaction mixture was cooled to room temperature, filtered through Celite, evaporated, re-evaporated from toluene, and the residue crystallised from dichloromethane to yield the subtitle compound, 4.0 g.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Br:13][C:14]1[CH:15]=[C:16]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-bromobenzenesulfonyl chloride according to METHOD A, using a Quest 210 apparatus and at 30° C., giving 1.16 g (27%) of an off-white solid: mp 155° C.; MS (Ionspray, [M+H]+) m/z 405; Anal. Calcd (found) for C13H13BrN2O4S2: C, 38.5 (38.4)%, H, 3.2 (3.0)%, N, 6.9 (6.6)%.
Reaction SMILES: C(=O)([S:3][CH2:4][CH2:5][C@H:6]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C:7](=[O:15])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14])C.C[O-].[Na+]>CO>[SH:3][CH2:4][CH2:5][C@H:6]([NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:7](=[O:15])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14]
Reactant: CC(=O)SCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCCCC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=CCCCCNC(=O)[C@H](CCS)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
A solution of (S)—S-3-(benzyloxycarbonylamino)-4-oxo-4-(5-oxopentylamino)butyl ethanethioate (195 mg, 0.494 mmol) in methanol (4 mL) was purged with argon for 10 min and then cooled to 0° C. Sodium methoxide in MeOH (25%, 0.12 mL) was added to the reaction. The mixture was stirred at 0° C. for 10 min. The reaction was quenched with saturated aqueous NH4Cl solution. The reaction was extracted with EtOAc (2×). The combined EtOAc extracts were washed with saturated aqueous NH4Cl solution, water, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The white solid residue was dried under vacuum to give (S)-benzyl 4-mercapto-1-oxo-1-(5-oxopentylamino)butan-2-ylcarbamate (150 mg, 0.426 mmol, 86% yield) as a white solid. Anal. Calcd. for C12H24N2O4S m/z 352.4. found: 353.23 (M+H)+.
Reaction SMILES: FC1C=CC(CCN2CCC(N3C4C(=CC=C([Br:23])C=4)CC3)CC2)=CC=1.[CH3:26][N:27]([CH3:36])[C:28]1[CH:33]=[CH:32][C:31](C=O)=[CH:30][N:29]=1>>[Br:23][C:31]1[CH:32]=[CH:33][C:28]([N:27]([CH3:36])[CH3:26])=[N:29][CH:30]=1
Reactant: CN(C)c1ccc(C=O)cn1
Reactant: Fc1ccc(CCN2CCC(N3CCc4ccc(Br)cc43)CC2)cc1
Product: CN(C)c1ccc(Br)cn1
Yield: 150.9 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline (0.5 g) and 2-dimethylamino-5-formylpyridine (0.345 g) were treated as in Example 130 to give the title compound (0.376 g) as a colorless oil (yield: 65.3%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.C1COCC1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[C:21]([O:27][CH3:28])[CH:20]=1>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[OH:24])=[C:21]([O:27][CH3:28])[CH:20]=1
Reactant: Brc1cccnc1
Reactant: COc1cc(Cl)ccc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1C(O)c1cccnc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
Toluene (3.5 mL) was added to a 3-necked flask and cooled to −60° C. n-BuLi (1.3 mL, 2.5M in hexanes) was added. A solution of 3-bromopyridine (0.3 mL, 3 mmol) in toluene (1.2 mL) was added dropwise to maintain internal temperature <−50° C. The resulting slurry was then stirred for 30 minutes at −60° C. THF (1.2 mL) was added dropwise, and the mixture was stirred for an additional 15 minutes. 4-Chloro-2-methoxy-benzaldehyde (561 mg, 3.3 mmol) was added and the mixture was allowed to warm to room temperature. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 201 mg (27%) of the title compound. MS (ESI) m/e 250 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[CH:16]=[C:15](B4OC(C)(C)C(C)(C)O4)[CH:14]=[C:13]([CH3:26])[CH:12]=3)[N:5]=2)[CH2:3][CH2:2]1.Br[C:28]1[S:32][CH:31]=[N:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC1CCCO1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[CH:16]=[C:15]([C:28]4[S:32][CH:31]=[N:30][CH:29]=4)[CH:14]=[C:13]([CH3:26])[CH:12]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(Nc2nccc(C3CC3)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Brc1cncs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC1CCCO1
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C3CC3)n2)cc(-c2cncs2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
To a solution of 4-cyclopropyl-N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine (750 mg, 2.14 mmol) in 2-methyl tetrahydrofuran (10.7 mL) were added 5-bromothiazole (406 mg, 2.35 mmol), PdCl2(dppf)-CH2Cl2 (87 mg, 0.11 mmol), and aqueous sodium carbonate (2 M, 2.14 mL). The reaction was sealed and purged with N2 for 5 minutes. The reaction was stirred at 80° C. for 16 h and cooled to room temperature. Water was added and extracted with EtOAc (3×). The combined organic layers were dried (magnesium sulfate), concentrated, and purified by flash chromatography to afford 4-cyclopropyl-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine (600 mg, 1.95 mmol, 91% yield) as an off-white solid. MS ESI: [M+H]+ m/z 309.1. 1H NMR (500 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.06 (s, 1H), 8.26 (d, 5.0, 1H), 8.19 (s, 1H), 8.04 (s, 1H), 7.43 (s, 1H), 7.10 (s, 1H), 6.82 (d, J=5.0, 1H), 2.29 (s, 3H), 2.00 (m, 1H), 1.17-0.93 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][NH2:15])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][NH:15][C:23](=[O:25])[CH3:24])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NCc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(3,4-dichlorophenyl)-1H-imidazole-4-methanamine (0.20 g, 0.83 mmol) in THF (30 ml) was added triethylamine (0.079 g, 0.78 mmol) and acetyl chloride (0.082 mg, 1.0 mmol). The reaction mixture was stirred at rt for 12 h. After evaporation of the solvent, the residue was dissolved in AcOEt and washed with H2O. The organic phase was dried (Na2SO4), concentrated and the obtained crude product was chromatographed [silica, elution with gradient CH2Cl2 to 100% (CH2Cl2/MeOH=9:1)]. The title compound was obtained as an off-white crystalline material (0.17 g, 74%). Mp. 177-180° C. (MeOH/CH2Cl2), MS: m/e=284 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10](I)[N:11]=1)[CH2:7][CH2:6][O:5]2.[Br-].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Zn+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2
Reactant: Clc1cc2c(cn1)-c1nc(I)cn1CCO2
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Clc1cc2c(cn1)-c1nc(-c3ccccn3)cn1CCO2
Temperature: 35 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
A mixture of 12-chloro-4-iodo-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (1.00 g, 2.88 mmol), pyridin-2-ylzinc(II) bromide (0.5 M THF) (8.60 mL), Pd(PPh3)4 (498 mg, 0.432 mmol) in THF (30 mL) was stirred at 35° C. for 16 hr. After removal of the solvent, the residue was washed with acetone to afford 12-chloro-4-(pyridin-2-yl)-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (750 mg, 87% yield) as yellow solid. LCMS (ESI) m/z: 299.0 [M+H+].
Reaction SMILES: O[CH2:2][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C-:8]1([CH2:13]O)[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:15].N1C=CC=CC=1.P(Cl)(Cl)[Cl:23]>C1COCC1>[Cl:23][CH2:2][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C-:8]1([CH2:13][Cl:23])[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:15]
Reactant: ClP(Cl)Cl
Reactant: OC[c-]1cccc1
Agent: [Fe+2]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: ClC[c-]1cccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask containing 1,1′-bis(hydroxymethyl)ferrocene (0.5 g, 2.0 mmol) under an atmosphere of nitrogen, was added THF (30 mL) and pyridine (0.33 mL, 4.1 mmol). PCl3 (0.35 mL, 4.1 mmol) was added dropwise to this solution and a yellow precipitate immediately formed. The mixture was stirred at room temperature for 3 hours. The yellow solution was decanted from the solid using a syringe and the remaining solid was washed with THF (2×15 mL). The washings and original solution were combined and evaporated to dryness. The resulting residue was used immediately in subsequent reactions.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[C:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])[NH2:30]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:36]3[CH:37]=[C:32]([CH:33]=[CH:34][CH:35]=3)[C:29]([NH2:30])=[O:31])[C:18]2=[O:27])=[CH:12][CH:11]=1)=[O:28]
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Product: NC(=O)c1cccc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)c1
Yield: 73 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3-carbamoylphenyl boronic acid instead of phenyl boronic acid, to obtain the title compound (73%).
Reaction SMILES: C[Si]([Br:5])(C)C.N(OC(C)(C)C)=O.N[C:14]1[S:15][C:16]2[C:21](=[O:22])[N:20]=[C:19]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[NH:18][C:17]=2[N:29]=1>C(#N)C>[Br:5][C:14]1[S:15][C:16]2[C:21](=[O:22])[N:20]=[C:19]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[NH:18][C:17]=2[N:29]=1
Reactant: C[Si](C)(C)Br
Reactant: CCCCCSc1nc(=O)c2sc(N)nc2[nH]1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCCCCSc1nc(=O)c2sc(Br)nc2[nH]1
Reaction time: 0.5 h

Procedure:
Trimethylsilyl bromide (0.44 mL) was added slowly to a solution at 0° C. under nitrogen of us t-butyl nitrite (0.42 mL) in acetonitrile (2 mL). After 30 minute at 0° C., 2-amino-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one (0.5 g) (product of Example 10) was added.
Reaction SMILES: C([O:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]3[CH:29]=[C:28](/[CH:30]=[CH:31]/[C:32]4[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=4)[CH:27]=[CH:26][N:13]3[C:14](=[O:25])[C:15]=2/[CH:16]=[CH:17]/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:5]1)=O.OC1CCCN(C2N=C3C=C(/C=C/C4SC=C(C(C)C)N=4)C=CN3C(=O)C=2/C=C/C(OC(C)(C)C)=O)C1>>[OH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]3[CH:29]=[C:28](/[CH:30]=[CH:31]/[C:32]4[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=4)[CH:27]=[CH:26][N:13]3[C:14](=[O:25])[C:15]=2/[CH:16]=[CH:17]/[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:5]1
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCC[C@@H](OC=O)C4)nc3c2)n1
Agent: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCCC(O)C4)nc3c2)n1
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCC[C@@H](O)C4)nc3c2)n1
Yield: 80.5 %

Procedure:
The tert-butyl (E)-3-{2-[(3R)-3-formyloxyhexahydro-1-pyridinyl]-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (488 mg, 0.886 mmol) obtained in (A) was treated in the same manner as in Example 102, (H) to obtain the title compound (373 mg, 81%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:6]([NH:16][C:17](=O)[CH2:18][C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[CH:5]=1.Cl>O1CCOCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:17]([CH2:18][C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[N:16][C:6]=2[CH:5]=1)=[O:26]
Reactant: CCC(CC)Nc1ccc(C(=O)OC)cc1NC(=O)Cc1ccc(Cl)s1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(CC)n1c(Cc2ccc(Cl)s2)nc2cc(C(=O)OC)ccc21
Yield: 77.3 %

Procedure:
0.99 g 3-[2-(5-Chloro-thiophen-2-yl)-acetylamino]-4-(1-ethyl-propylamino)-benzoic acid methyl ester were reacted with 10 ml of 4M hydrochloric acid in dioxane in a microwave reactor at 130° C. for 15 min. The reaction was concentrated. The residue was dissolved in ethyl actate, washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulphate and concentrated to yield 0.73 g (77%) of 2-(5-Chloro-thiophen-2-ylmethyl)-1-(1-ethyl-propyl)-1H-benzoimidazole-5-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]2[C:19]([CH3:24])=[N:20][O:21][C:22]=2[CH3:23])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:27][N:28]([CH3:33])[S:29](Cl)(=[O:31])=[O:30].O>CN(C=O)C>[CH3:24][C:19]1[C:18]([C:10]2[N:11]([S:29]([N:28]([CH3:33])[CH3:27])(=[O:31])=[O:30])[C:12]3[C:17]([C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:22]([CH3:23])[O:21][N:20]=1
Reactant: COc1ccc(-c2c(-c3c(C)noc3C)[nH]c3ccccc23)cc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3c(C)noc3C)n(S(=O)(=O)N(C)C)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(3-(4-methoxyphenyl)-1H-indol-2-yl)-3,5-dimethylisoxazole (the intermediate product of step (d) from Example 1, 35 mg, 0.11 mmol) was added to a suspension of NaH (25 mg, 60% in heptane) in DMF (dry, 0.7 ml) at 0° C. under nitrogen. The mixture was stirred at rt for 30 min and was then cooled to 0° C. again. Dimethylsulfamoyl chloride (2 eq) was added drop wise. The mixture was stirred at rt for 2 h, cooled to 0° C. and water was added to quench the reaction. Extraction with DCM using isolute phase separator and concentration of the combined organic layers afforded 2-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-N,N-dimethyl-1H-indole-1-sulfonamide in quantitative yield.