Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].Br[CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1COCC1>[Br:3][C:4]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1cccc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(NCCO[Si](C)(C)C(C)(C)C)c1Br
Reaction time: 0.25 h

Procedure:
To a stirred slurry of NaH (60% in mineral oil) (0.435 mL, 10.00 mmol) in THF (5 ml) was added dropwise a solution of 2-bromo-3-methylaniline (0.625 mL, 5 mmol) in THF (1 ml). After 15 min, (2-bromoethoxy)-tert-butyldimethylsilane (1.07 mL, 5 mmol) was added and the reaction mixture was stirred for 48 h. The reaction was quenched with water, partitioned between EtOAc and aqueous saturated ammonium chloride. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (0-10% EtOAc/hexanes). 2-Bromo-N-(2-(tert-butyldimethylsilyloxy)ethyl)-3-methylaniline was isolated as a yellow oil.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:32]5[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN5CCNCC5)c4)cc23)CC1
Yield: 19.6 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (15.0 mg, 0.034 mmol), piperazine (3.5 mg, 0.04 mmol) and NaBH(OAc)3 (23.0 mg, 0.102 mmol) were reacted to give the title compound (3.4 mg, 19.7%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].C(=O)(O)[O-].[Na+].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[C:12]1([S:18]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)NNS(=O)(=O)c1ccccc1

Procedure:
180 g. (0.2 mole) of methyl carbazate (from hydrazine and dimethyl carbonate) is placed in a liter flask. 20.0 g (0.24 mole) of sodium bicarbonate and 100 ml. water are added. The mixture is stirred and dropped in 35.2 g. (0.2 mole) of benzene sulfonyl chloride. Then the mixture is stirred for 16 hours. The crystals that have formed are filtered off, washed with water, and dried in air. Yield = 34.5g.; m.p. 149°-154° C. Upon recrystallization from ethanol 26 g. of material is recovered which melts sharply at 155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH3:17]
Reactant: CCOC(=O)C(C)=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CCOC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13]1([S:19]([CH2:22][CH2:23][CH2:24][CH2:25]Br)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19]([CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]3)=[CH:4][CH:3]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(CCCCBr)c1ccccc1
Reactant: O=C1CCc2ccc(O)cc2N1
Product: O=C1CCc2ccc(OCCCCS(=O)(=O)c3ccccc3)cc2N1

Procedure:
Prepared analogous to Example 4 from 7-hydroxy-3,4-dihydro-carbostyril (see N. Shigematsu et al., Chem. Pharm. Bull. 1961, 970-975) and 4-phenylsulfonyl-butyl bromide.
Reaction SMILES: ClC1C(N[C@H]2CCC[C@@H]2N[C:19]([C:21]2[C:26]([N:27]3[N:31]=[CH:30][CH:29]=[N:28]3)=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])=NC=C(C(F)(F)F)C=1.Cl.[CH2:33]([C:35]1[C:36]([NH:45][C@H:46]2[CH2:50][CH2:49][CH2:48][C@@H:47]2[NH2:51])=[N:37][CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:40]=1)[CH3:34].N1N(C2C(C(O)=O)=NC=CC=2)N=CC=1>>[CH2:33]([C:35]1[C:36]([NH:45][C@H:46]2[CH2:50][CH2:49][CH2:48][C@@H:47]2[NH:51][C:19]([C:21]2[C:26]([N:27]3[N:31]=[CH:30][CH:29]=[N:28]3)=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])=[N:37][CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[N:40]=1)[CH3:34]
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl)c1ncccc1-n1nccn1
Reactant: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1N
Agent: Cl
Agent: O=C(O)c1ncccc1-n1nccn1
Product: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{ [3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 122) from (1S,2S)-1-N-[3-ethyl-5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 41; 266 mg, 0.86 mmol) and 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 179 mg, 0.94 mmol) except this was further purified by reverse phase chromatography (C18 silica, 5-100% water (with 0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][C:23]=1[NH2:24]>>[NH2:24][C:23]1[CH:25]=[C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:27]=[CH:28][C:22]=1[F:21]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2ccc(F)c(N)c2)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(F)c(N)c3)ccn2c1=O
Yield: 102.8 %

Procedure:
Methyl 8-(3-amino-4-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (122 mg, 0.51 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (128 mg, 98%). ESI-MS m/z: 367 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[NH2:26][CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:26][CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)=[O:20]
Reactant: NCc1ccc2ccccc2c1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc2ccccc2c1)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.4 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (0.800 g, 2.20 mmol), 2-aminomethylnaphthalene (0.380 g, 2.42 mmol), triethylamine (0.240 g, 2.37 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'(2-naphthylmethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.200 g, 17.5% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:10][O:11][C:12]([NH:14][C:15](=NC(OC)=O)SC)=[O:13]>CO.C(O)(=O)C>[CH3:10][O:11][C:12](=[O:13])[NH:14][C:15]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=2[N:1]=1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: Nc1ccc(O)cc1N
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Nc1nc2cc(O)ccc2[nH]1
Yield: 109.7 %

Procedure:
6 g of 3,4-diaminophenol were combined with 9.8 g of 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea in 50 ml methanol and 30 ml acetic acid. The reaction mixture was refluxed for 4 hours. Solvents were then evaporated under reduce pressure yielding 10.8 g crude (5-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid methyl ester. The residue was subjected to flash chromatography eluting with a mixture of dichloromethane-methanol (9:1; v/v) to give 5.6 g of a beige solid. Mass spectrum: 208 [M+H]+, retention time=0.56 minute.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:49][NH:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:51]([N:50]([CH3:49])[C:23]([C:18]1[NH:19][C:20]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:12]([N:9]1[CH2:8][CH2:7][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:11][CH2:10]1)=[O:13])=[CH:22][CH:21]=2)=[O:25])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CNCc1ccccc1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccccc1)C(=O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), methylbenzylamine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[C:4]([F:13])[C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[NH2:19]>>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([NH:19][C:18]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:16]([OH:15])[CH:17]=2)(=[O:10])=[O:9])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14]
Reactant: O=S(=O)(Cl)c1cc(Br)c(F)c(F)c1F
Reactant: COc1ccc(N)cc1O
Product: COc1ccc(NS(=O)(=O)c2cc(Br)c(F)c(F)c2F)cc1O

Procedure:
1-Bromo-2,3,4-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)amino-sulfonyl]benzene and 1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)amino-sulfonyl]benzne were prepared in a manner similar to that described above, beginning with a mixture of 5-bromo-2,3,4-trifluorophenylsulfonyl chloride (Example B) and2-bromo-3,4,5-trifluorophenylsulfonyl chloride (Example C) and 3-hydroxy4-methoxyaniline. The two isomeric compounds were separated by column chromatography (silica gel; ethyl acetate:hexanes, 1:4). 1H-NMR (CDCl3): δ 7.79 (1H, m), 6.72-6.62 (4H, m), 5.65 (1H, s), 3.85 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([N:10]=[S:11]([C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)([CH3:13])=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=1.[C:25]([C:27]1[CH:28]=[C:29]([NH:33][C:34]([C:36]2[N:40]([CH3:41])[N:39]=[C:38]([CH3:42])[CH:37]=2)=[O:35])[CH:30]=[CH:31][CH:32]=1)#[CH:26]>>[CH3:41][N:40]1[C:36]([C:34]([NH:33][C:29]2[CH:28]=[C:27]([C:25]#[C:26][C:2]3[CH:3]=[C:4]([C:8]([N:10]=[S:11]([C:14]4[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=4)([CH3:13])=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=3)[CH:32]=[CH:31][CH:30]=2)=[O:35])=[CH:37][C:38]([CH3:42])=[N:39]1
Reactant: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Reactant: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)c2cncc(Br)c2)c1
Product: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1

Procedure:
In a manner similar to that described in Example 460, methyl (3-{N-[(5-bromopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}phenyl)acetate (202 mg, 0.492 mmol) and N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (153 mg, 0.64 mmol), were converted to the title compound as a light yellow solid foam (275 mg, 98%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22](=[O:29])OCC(Cl)(Cl)Cl)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>CCCCCC.C(OCC)(=O)C>[OH:34][CH2:33][C:32]([NH:31][C:22]([NH:21][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[C:14]=2[C:15]=1[CH3:30])=[O:29])([CH3:36])[CH3:35]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Reactant: CC(C)(N)CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)NC(C)(C)CO)C(c1ccc(C(C)C)cc1)CO2
Yield: 39 %

Procedure:
Using 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 2-amino-2-methyl-1-propanol, the title compound was synthesized in the same manner as in Example 143. Yield: 39%. Melting point: 157-158° C. (hexane-ethyl acetate).
Reaction SMILES: [H][H].[C:3]([O:11][CH3:12])(=[O:10])[CH2:4][CH2:5][C:6](OC)=O>[Mn].[Cu]>[OH:10][CH2:3][CH2:4][CH2:5][CH2:12][O:11][CH:3]1[CH2:4][CH2:5][CH2:6][O:10]1
Reactant: COC(=O)CCC(=O)OC
Reactant: [H][H]
Agent: [Cu]
Agent: [Mn]
Product: OCCCCOC1CCCO1

Procedure:
This second intermediate reaction product stream is then passed on through lines 20, 21, and 22 to third hydrogenation reactor 10. Additional hydrogen at an appropriate temperature can, if desired, be added from line 23 to the second intermediate reaction product mixture in line 21 in order to adjust the temperature of the resulting stream prior to entry to third hydrogenation reactor 10. This third hydrogenation reactor 10 contains a charge 24 of the manganese promoted copper hydrogenation catalyst DRD92/89A which is also available from Kvaerner Process Technology Limited. This catalyst is highly active for the conversion of the remaining dimethyl succinate but exhibits the surprising result that the content of the cyclic acetal, i.e. 2-(4′-hydroxybutoxy)-tetrahydrofuran, in the final product stream in line 25 is much reduced compared with the content of this compound in the second intermediate reaction product stream in line 19.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[C:16]([NH:24][C:25]([NH:15][C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(N)cc(-c2ccccc2)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: COc1cc(NC(=S)NC(=O)c2ccccc2)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.2 %

Procedure:
5-Methoxy-biphenyl-3-ylamine (129 mg, 0.65 mmol) are dissolved in acetone (5 ml) and slowly treated with a solution of benzoyl isothiocyanate (0.096 ml, 0.71 mmol) in acetone (2 ml). After stirring at ambient temperature for 18 h, the solvent is removed in vacuo and the residue crystallized from hexane. The product (203 mg, 86%) is obtained as colorless crystalls. Mp 149° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[C:9]1([C@@H:15]([NH2:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CS(C)=O>C(OCC)(=O)C>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:17][C@H:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:16])[CH:7]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: Fc1cc(I)ccn1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(I)ccn1)c1ccccc1
Temperature: 25 °C

Procedure:
The mixture of 1 g of 2-fluoro-4-iodopyridine (synthesized according to a method disclosed in J. Org. Chem. 1993, 58, 7832-7838), 1.73 mL of (1S)-1-phenylethylamine, and 20 mL of dimethylsulfoxide, was stirred overnight at 80° C. The reaction mixture was cooled back to room temperature, then diluted with ethyl acetate, and washed with water and saturated brine in the subsequent order. The obtained organic layer was dried over anhydrous magnesium sulfate, then the insolubles were filtered, the filtrate was concentrated under reduced pressure, and the thus obtained residue was purified by silica gel column chromatography, to obtain 744 mg of 4-iodo-N-[(1S)-1-phenylethyl]-2-pyridinamine [58-1] as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][OH:38]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:36][CH2:37][OH:38])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 338) (80 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (89 mg) and 2-bromoethanol (0.05 ml) were added to the solution, and the mixture was stirred at 70° C. overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (77 mg, yield 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11](=[O:23])[NH:12][C:13](=[O:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].CO.[C]=O.C(N(CC)CC)C.[C:35]([O:38][CH2:39]C)(=[O:37])C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11](=[O:23])[NH:12][C:13](=[O:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([C:35]([O:38][CH3:39])=[O:37])=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NC2=C(c3ccc(I)cc3)C(=O)NC2=O)cc1F
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: [C]=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(C2=C(Nc3ccc(C)c(F)c3)C(=O)NC2=O)cc1

Procedure:
A mixture of 3-(3-Fluoro-4-methylphenyl-amino)-4-(4-iodophenyl)-1H-pyrrole-2,5-dione (Example A705, 126 mg, 0.3 mmol), tetrakis(triphenyl phosphine)-palladium(0) (35 mg, 0.03 mmol) and methanol (10 mL) was placed in a 50 mL two necked round bottomed flask. One arm of the flask was sealed with a septum and to the other arm was fitted a reflux condenser, topped with a multiway tap connected respectively to vacuum, a carbon monoxide cylinder and to a balloon. Using the multiway tap, the flask was alternately evacuated and flushed with carbon monoxide, and the process repeated several times to unsure an atmosphere of carbon monoxide within the flask. The balloon was charged with carbon monoxide and this was then opened to the reaction flask for the duration of the reaction in order to maintain a slight positive pressure of carbon monoxide within the flask. Triethylamine (100 uL, 0.7 mmol) was added and the mixture heated at reflux for 16 hours. The mixture was cooled and diluted with ethyl acetate and the resulting solution washed with aqueous hydrochloric acid (1M, 50 mL), water (50 mL) and brine (50 mL). The organic solution was dried over magnesium sulphate and evaporated to afford a solid. This was chromatographed on silica gel using dichloromethane-ether (98:2 v/v) as eluent to afford the tide compound, a solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=O)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]2)=[N:19][CH:20]=1>>[C:10]([O:28][C:27]([N:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:11]([C:8]3[S:7][C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=4[CH:9]=3)=[O:13])=[CH:20][N:19]=2)[CH2:22][CH2:23]1)=[O:29])([CH3:2])([CH3:9])[CH3:6]
Reactant: O=C(O)c1cc2c(Cl)cccc2s1
Reactant: Nc1ccc(N2CCN(C(=O)O)CC2)nc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3cc4c(Cl)cccc4s3)cn2)CC1

Procedure:
This compound was prepared from 4-chloro-benzo[b]thiophene-2-carboxylic acid and 4-(5-amino-pyridin-2-yl)-piperazine-1-carboxylic acid tort-butyl ester as described in the preparation of the intermediate section. LCMS for C23H25ClN4O3S calcd. (m/e) 472, observed 471 (M−H).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[F:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[F:14])[NH2:10].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.Cl>CC(O)CC.C1COCC1>[F:14][C:13]1[CH:12]=[C:11]2[C:9](=[CH:8][C:7]=1[F:6])[N:10]=[C:3]([CH3:4])[CH:2]=[CH:1]2
Reactant: C/C=C/C=O
Reactant: Nc1ccc(F)c(F)c1
Agent: Cl
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CCC(C)O
Solvent: C1CCOC1
Product: Cc1ccc2cc(F)c(F)cc2n1
Temperature: 0 °C
Yield: 56.7 %

Procedure:
Crotonaldehyde (226.34 g, 3.23 tool) in 100 mL of 2-butanol was added dropwise to a refluxing solution of 3,4-difluoroaniline (417.27 g, 3.23 tool), p-chloranil (794.65 g, 3.23 mol) and HCl conc. (808 mL) in 5.4 L of 2-butanol. After 2 hours of heating 2.7 L of solvent was removed under vacuum at ca. 60° C. Then 2 L of toluene was added to the reaction mixture followed by removal of 2.5-3 L of solvent until a very pasty solid formed. THF (2L) was added and the mixture heated 30 min. after which it was cooled to 0° C. The solid was collected and washed with THF until pure by tlc. The solid was then dissolved in aq. K2CO3 /EtOAc and the organic phase separated. The aqueous phase was extracted with EtOAc (2X) and the organic phases combined, dried over MgSO4, and the solvent removed. The product was crystallized in the minimum amount of EtOAc to give 328.08 g (57%) of the title compound.