Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH:16]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH2:16][NH:18][CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1Cc2ccccc2C1
Reactant: O=CCCC1CCCCN1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(CN2CCCCC2CCCNC2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 23 (820 mg, 3.55 mmol) in DCM (15 mL) was added 2-amino-indane (472 mg, 3.55 mmol) drop-wise at ice cold conditions. Acetic acid (0.2 mL) was added to the reaction mixture, followed by sodium triacetoxy borohydride (2.2 g, 10.65 mmol) portion-wise at ice cold conditions. The reaction mixture was stirred at rt for 16 hours. The reaction mixture was diluted with DCM, washed with saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by 230-400 silica gel column chromatography using 1-3% MeOH-DCM as eluent to yield compound 24.
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C=O.N1CCCC[CH2:19]1>C(OCC)(=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:2]([C:3](=[CH2:19])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:1])[CH:11]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)CCC(=O)c1cccnc1
Agent: C=O
Solvent: CCOC(C)=O
Product: C=C(CC(=O)OCC)C(=O)c1cccnc1
Yield: 53.9 %

Procedure:
A solution of ethyl 4-oxo-4-(3-pyridyl)butanoate (4 g), 37% aqueous formaldehyde (2.46 g) and piperidine (2.46 g) was stirred at room temperature for 18 h. The reaction mixture was diluted with 200 mL of ethyl acetate and washed with water (2×100 mL). The reaction mixture was concentrated and dissolved in ethanol (10 mL) and treated with 4N HCl/dioxane (4 mL) at 80° C. for 12 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), saturated sodium bicarbonate solution (2×100 mL), concentrated and purified on flash chromatography (20% Ethyl acetate to 80% ethyl acetate in hexane) to give 2.28 g of the title compound, ESMS (M+1)+220.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1O.COC1C=CC(C(Cl)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>N1C=CC=CC=1.ClCCl>[F:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:8]1
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1F
Agent: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.244 gms. (20 mMoles) of 5-fluorouridine is dissolved in 20 mL anhydrous pyridine and then dried under vacuum. This procedure is repeated at least one more time in order to make 5-fluorouridine devoid of moisture. The dried 5-fluorouridine is then dissolved in 20 mL of pyridine. 8.131 gms (24 mMoles, 1.2 eq.) of 4,4'-dimethoxy trityl chloride is added as solid in 4 fractions over a period of 2 hours. The reaction mixture is then stirred at room temperature overnight and is then diluted with 25 mL of dichloromethane and washed with saturated sodium bicarbonate solution. The aqueous layer is then washed with 20 mL dichloromethane. The organic layers are mixed and washed with saturated bicarbonate solution two more times. The organic layer is then dried over anhydrous sodium sulphate. The solvent is removed under vacuum to yield a yellow foam which is purified on a silica gel column using 90:10 chloroform:methanol as eluent. The 4, 4'-dimethoxytrityl derivative of 5-fluorodeoxyuridine is prepared in an analogous manner.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[S:8])[NH:6][C:5]2[CH:9]=[CH:10][N:11]=[CH:12][C:4]=2[S:3]1(=[O:14])=[O:13].[C:15](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH3:1][N:2]1[C:7]([S:8][CH3:15])=[N:6][C:5]2[CH:9]=[CH:10][N:11]=[CH:12][C:4]=2[S:3]1(=[O:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CN1C(=S)Nc2ccncc2S1(=O)=O
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CSC1=Nc2ccncc2S(=O)(=O)N1C
Reaction time: 1 h

Procedure:
A solution of 2-methyl-3-thioxo-2,3-dihydro-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (1.0 g) in acetonitrile (20 mL) was supplemented with potassium carbonate (1.0 g), then with methyl iodide (1 mL). After 1 h at room temperature, the solvent was removed by distillation under reduced pressure. The residue was dispersed in water (50 mL) and the suspension was adjusted to pH 5 with formic acid. The insoluble material was collected by filtration, washed with water and dried (yield: 0.8 g); m.p. 135°-138° C. (Compound V).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:25])[NH:7][C:6]=2[CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[F:30][C:31]1[C:36]([F:37])=[C:35]([F:38])[C:34](B(O)O)=[CH:33][CH:32]=1>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:8]3[NH:9][C:10]4[C:2]([C:33]5[CH:32]=[C:31]([F:30])[C:36]([F:37])=[C:35]([F:38])[CH:34]=5)=[CH:3][C:4]([C:26]([F:29])([F:27])[F:28])=[CH:5][C:6]=4[N:7]=3)[C@H:12]([CH3:25])[CH2:13]2)=[N:18][CH:19]=[C:20]([Cl:24])[CH:21]=1
Reactant: OB(O)c1ccc(F)c(F)c1F
Reactant: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2c(Br)cc(C(F)(F)F)cc2[nH]1
Product: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
4-Bromo-2-[(2R)-4-(3,5-dichloro-pyridin-2-yl)-2-methyl-piperazin-1-yl]-6-trifluoromethyl-1H-benzoimidazole (204 mg, 0.4 mmol, Example 149b) and 4,5,6-trifluorophenylboronic acid (141 mg, 0.8 mmol, Aldrich) reacted under the conditions of Example 158 to give the title compound. MS (ESI, pos. ion) m/z: 504 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[C:32]1(B(O)O)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:40]4[C:41]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:37]=[CH:38][CH:39]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: OB(O)c1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccc5ccccc45)cc3)oc2C)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl-propionic acid ethyl ester (0.907 mmol) (see Ex. 2, part B) and 1-naphthaleneboronic acid (0.998 mmol) in toluene:ethanol (18.2 mL of a 1:1 solution) was treated with Na2CO3(aq) (0.906 mL of a 2M solution). A nitrogen atmosphere was applied, Pd(PPh3)4 (52.5 mg) was added, and the orange mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (20 mL) and H2O (30 mL). The layers were separated, and the aqueous phase was back-extracted with ethyl acetate (2×10 mL). Combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (20 g SiO2, 3:7 ethyl acetate:hexanes) to give the desired product in 87% as an orange oil; Rf=0.46 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=8 Hz, 2H), 7.92-7.82 (m, 3H), 7.59-7.40 (m, 6H), 6.81-6.72 (m, 4H), 4.22-4.17 (m, 4H), 2.98 (t, 2H), 2.38 (s, 3H), 1.46 (s, 6H), 1.22 (t, 3H); MS (EI) 536.3 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH2:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:25][C:22]([CH3:24])([CH3:23])[CH2:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[C@H:6]([C:12]#[N:13])[CH2:7][CH2:8]1)#[CH:11]
Reactant: CC(C)(N)Cc1ccc(F)cc1
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC(C)(C)Cc1ccc(F)cc1
Reaction time: 48 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.05 g, 0.25 mmol, Example 8D) in acetonitrile (3 mL) at room temperature under nitrogen was added 1-(4-fluorophenyl)-2-methyl-2-propylamine (0.09 g, 0.508 mmol). The reaction mixture was stirred for two days and then concentrated under reduced pressure. The residue was flash chromatographed with 1-2% MeOH/CH2Cl2 to provide the desired compound as a white powder. MS (DCI) m/z 328 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.01-2.04(2H, m), 2.05 (2H, s), 2.07 (2H, s), 3.03 (1H, m), 3.04 (6H, s), 3.5-4.57 (2H, m), 4.57-4.58 (1H, m), 4.58-5.59 (1H, m), 7.0-7.03 (4H, m).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1.[Br:21]N1C(=O)CCC1=O.CSC>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:21])=[CH:4][C:3]=1[O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: OCc1ccc(I)c(Oc2ccc3ccccc3c2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CSC
Product: BrCc1ccc(I)c(Oc2ccc3ccccc3c2)c1
Temperature: 25 °C

Procedure:
To a solution of [4-iodo-3-(naphthalen-2-yloxy)-phenyl]-methanol (0.085 g, 0.226 mmol) in CH2Cl2 (2 mL) at −15° C. was added a cold (0° C.) solution of N-bromosuccinimide (0.120 g, 0.68 mmol) in dimethyl sulfide (0.060 mL, 0.814 mmol) with stirring. The reaction mixture was allowed to warm to ambient temperature overnight, concentrated to dryness, and chromatographed (SiO2, 10% EtOAc:hexane) to give the title compound which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:5][CH:4]=1.C([Sn](=O)CCCC)CCC.C[Si]([N:46]=[N+:47]=[N-:48])(C)C.C(O)CO>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]4[NH:48][N:47]=[N:46][N:25]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCCCC#N)c23)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: OCCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCCCc4nnn[nH]4)c23)cc1
Reaction time: 1 h

Procedure:
Stir 1.00 g (2.1 mmol) 6-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}hexanenitrile, 0.79 g (3.2 mmol) di-n-butyltin oxide and 3.68 g (32 mmol) trimethylsilylazide in 44 ml toluene overnight at 80° C. Then add 1 ml ethylene glycol, stir for 1 h under reflux and then concentrate by evaporation. Take up the residue in ethyl acetate, wash with dilute hydrochloric acid and with sodium chloride solution, dry, and concentrate by evaporation. Purify the raw product by RP-HPLC (column: Gromsil 250 mm×40 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-50 min 5%→98% acetonitrile, 50-55 min 98% acetonitrile). Crystallize the combined product fractions from diethyl ether. 372 mg (38% of theor.) of the title compound is obtained as beige crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.C1C(=O)N([Cl:20])C(=O)C1.O>C(#N)C>[Cl:1][C:2]1[C:10]([Cl:20])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(Cl)ccc1C(=O)O
Solvent: CC#N
Solvent: O
Product: COc1cc(Cl)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 549 %

Procedure:
A mixture of 4-chloro-2-methoxybenzoic acid (10 g, 53.6 mmol) and NCS (35 g, 19.2 mmol) in acetonitrile (200 mL) was stirred at room temperature for 48 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to get the crude product (23.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1.C(N(CC)CC)C.[NH2:23][CH2:24][C:25]1([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:24][C:25]3([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: NCC1(O)CCCC1
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cnc2cc(Br)cnc2c1NCC1(O)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine (54.42 g, 188.6 mmol) in chloroform (820 mL) was cooled to 0° C., and triethylamine (105 mL, 755 mmol) was added. A solution of 1-(aminomethyl)cyclopentanol (28.25 g, 245.2 mmol) in chloroform (272 mL) was added slowly over a period of 15 minutes. The reaction was allowed to warm to room temperature and stirred for 30 minutes. The solution was washed sequentially with water (500 mL) and saturated aqueous sodium bicarbonate (750 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 1-{[(7-bromo-3-nitro[1,5]naphthyridin-4-yl)amino]methyl}cyclopentanol.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38](Cl)[C:37]=3[CH3:43])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].C1(P(C2CCCCC2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:57]2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O1CCCC1.CN1CCCC1=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([CH2:57][CH:52]4[CH2:53][CH2:54][CH2:55][CH2:56][CH2:51]4)[C:37]=3[CH3:43])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: Cc1c(Cl)cccc1-c1ccc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)nc1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1c(CC2CCCCC2)cccc1-c1ccc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)nc1C(=O)OC(C)(C)C

Procedure:
A mixture of EXAMPLE 107A (60 mg), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos, 4.58 mg) and tris(dibenzylideneacetone)dipalladium(0) (2.25 mg) in tetrahydrofuran (0.5 mL) and 1-methyl-2-pyrrolidinone (0.5 mL) was stirred at room temperature for 5 minutes while bubbling N2 through the reaction mixture. To this solution was added 0.5 M (cyclohexylmethyl)zinc(II) bromide (0.393 mL) at room temperature. The reaction mixture in a sealed tube was heated in a preheated oil bath at 100(C overnight and cooled. The reaction mixture was quenched with water and diluted with dichloromethane. The dichloromethane layer was washed with water and concentrated. The residue was purified by flash chromatography, and eluted with 5% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:27][C:12]2=[CH:13][C:14]3[C:15](=[O:26])[N:16]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([CH2:35][C@@H:36]([NH2:38])[CH3:37])[CH:34]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([CH2:35][CH:36]([NH:38][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:9]2[NH:27][C:12]3=[CH:13][C:14]4[C:15](=[O:26])[N:16]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:17](=[O:20])[C:18]=4[CH:19]=[C:11]3[N:10]=2)[CH3:37])[CH:34]=1
Reactant: Cc1ccc(F)cc1C[C@H](C)N
Reactant: CN(C)CCN1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Yield: 84.3 %

Procedure:
2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.05 g, 2.72 mmol), (S)-1-(5-fluoro-2-methylphenyl)propan-2-amine (0.55 g, 3.26 mmol), n-butanol (50 mL) and N,N-diisopropylethylamine (5 mL) were mixed together in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Solvents were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a brown solid product, 1.18 g, 84.3% yield. MS: 517.2 [M+H]+. 1H NMR (DMSO-d6, 300 MHz): δ 13.42 (s, 1H), 11.23 (s, 1H), 10.86 (d, 1H, J=8.1 Hz), 8.13 (s, 1H), 8.00 (s, 1H), 7.31-7.10 (m, 3H), 6.90-6.83 (m, 1H), 6.14 (d, 1H, J=7.5 Hz), 4.22-4.13 (m, 1H), 3.68 (t, 2H, J=6.5 Hz), 3.00 (d, 2H, J=6.9 Hz), 2.51-2.47 (m, 2H), 2.42 (s, 3H), 2.18 (s, 6H), 1.34 (d, 3H, J=6.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([OH:12])[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: O=C1Nc2c(Br)cccc2C1=O
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1Nc2c(Br)cccc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 24 h

Procedure:
7-bromoisatin (0.113 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 24 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[CH2:17][C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21]N(C)C=O.S(Cl)(Cl)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(CC(=O)O)c1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Cc1cc(C#N)ccc1OCc1ccccc1

Procedure:
10.0 g (0.037 mol) of (2-benzyloxy-5-cyano-phenyl)-acetic acid are refluxed for two hours in 65 ml dichloromethane, 0.1 ml of dimethylformamide and 8.1 ml (0.11 mol) of thionyl chloride. Then the mixture is concentrated by evaporation, the residue is combined with 55 ml of methanol and refluxed for one hour. After cooling the mixture is suction filtered, washed with ether/petroleum ether and dried at 50° C.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1)=O.[C:21](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1)#[CH:21]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under argon, tert-butyl 4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (600 mg) was dissolved in methanol, and potassium carbonate (839 mg) and dimethyl 1-diazo-2-oxopropylphosphonate (786 mg) were added. The mixture was stirred at room temperature for 3 hours. After aqueous work-up, the mixture was extracted with ethyl acetate, the extracts were dried with sodium sulphate and the solvent was concentrated under reduced pressure. The residue was purified chromatographically. This gave tert-butyl 4-(4-ethynyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (493 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.Br[CH2:25][C:26]([NH2:28])=[O:27]>>[C:19]([C:12]1[CH:11]=[C:10]2[C:15]([C:16]3[C:17](=[O:18])[C:5]4[CH:4]=[CH:3][C:2]([O:1][CH2:25][C:26]([NH2:28])=[O:27])=[CH:23][C:6]=4[C:7]([CH3:21])([CH3:22])[C:8]=3[NH:9]2)=[CH:14][CH:13]=1)#[N:20]
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: NC(=O)CBr
Product: CC1(C)c2cc(OCC(N)=O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and 2-bromo-acetamide.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[C:22]([Cl:23])=[C:21]([Cl:24])[C:20]([Cl:25])=[C:19]([Cl:26])[C:15]=2[C:16]([OH:18])=[O:17])=O)=[C:4]1[CH3:27])[CH3:2].[CH2:28]([N:30]([CH2:42][CH3:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[CH:32]=1)[CH3:29]>C(OC(=O)C)(=O)C>[CH2:38]([N:37]([CH2:40][CH3:41])[C:33]1[CH:32]=[C:31]([N:30]([CH2:28][CH3:29])[CH2:42][CH3:43])[CH:36]=[CH:35][C:34]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:27])[C:14]2[C:15](=[C:19]([Cl:26])[C:20]([Cl:25])=[C:21]([Cl:24])[C:22]=2[Cl:23])[C:16](=[O:18])[O:17]1)[CH3:39]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3c(C)n(CC)c4ccccc34)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(N(CC)CC)c1

Procedure:
Following a procedure similar to that described in part B of Example 2 above, 4.45 g (0.01 mole) of 2-(1-ethyl-2-methyl-3-indolyl)carbonyl-3,4,5,6-tetrachlorobenzoic acid and 2.20 g (0.01 mole) of N,N,N',N'-tetraethyl-m-phenylenediamine were interacted in the presence of ten ml of acetic anhydride to obtain 3-[2,4-bis(diethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)-4,5,6,7-tetrachlorophthalide (Formula III: R0 =R1 =R2 =R3 =Cl; R=R6 =CH2CH3 ; R4 =N(CH2CH3)2 ; R5 =CH3 ; Y1 =H) melting at 100°-103° C. and showing a significant infrared absorption maxima at 1770 cm-1 (C=O; s). A toluene solution of this compound developed an intense blue color when spotted on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][OH:10])[CH:3]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](Br)([F:20])[F:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH2:9][OH:10])=[CH:14][CH:13]=1
Reactant: OCc1cc(F)ccc1O
Reactant: FC(F)(Br)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: OCc1cc(F)ccc1OC(F)(F)c1ccc(Br)cc1
Yield: 35.8 %

Procedure:
A suspension of 1.17 g (8.23 mmol) of 4-fluoro-2-(hydroxymethyl)phenol from Example 34A, 2.59 g (12.63 mmol) of 1-bromo-4-[bromo(difluoro)methyl]benzene from Example 33A and 1.25 g (9.06 mmol) of potassium carbonate in 10 ml of 2-propanol is heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is suspended in methylene chloride, absorbed on silica gel, dried in vacuo and purified by chromatography (mobile phase: cyclohexane/ethyl acetate 10:1, then 100% ethyl acetate). 1.02 g (2.95 mmol, 35% yield) of the title compound are obtained.