Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH:21]3[CH2:24][CH:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:22]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O:34]CC)=[O:33].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:31])[NH:20][CH:21]3[CH2:22][CH:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:24]3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CC(c5ccccc5)C4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NC1CC(c2ccccc2)C1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(3-phenylcyclobutylcarbamoyl)phenoxy)chroman-4-carboxylate (0.086 g, 0.17 mmol) in 3:1 THF/ethanol (4 ml) was added 1M sodium hydroxide (0.36 ml, 0.36 mmol), and the reaction was stirred overnight. The reaction was concentrated, taken up in water, acidified with 1M hydrochloric acid, and extracted twice with EtOAc. The combined organic layers were washed with saturated sodium chloride, dried over Na2SO4, filtered, and concentrated to yield 67 mg of the title compound (82% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Br:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:41]([OH:43])=O)=[CH:34][N:35]2[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1.[NH2:44][C:45]1[S:46][CH:47]=[CH:48][N:49]=1>C(Cl)Cl>[S:46]1[CH:47]=[CH:48][N:49]=[C:45]1[NH:44][C:41]([C:33]1[C:32]2[C:36](=[CH:37][C:29]([Br:28])=[CH:30][CH:31]=2)[N:35]([CH:38]([CH3:39])[CH3:40])[CH:34]=1)=[O:43]
Reactant: CC(C)n1cc(C(=O)O)c2ccc(Br)cc21
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)n1cc(C(=O)Nc2nccs2)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 11.6 %

Procedure:
A solution of triphenylphosphine (2.42 mg, 9.22 mmol) in methylene chloride (25 mL) cooled to 0° C. was treated with N-bromosuccinimide (1.64 mg, 9.22 mmol). The reaction was stirred at 0° C. for 15 min. At this time, the reaction was treated with 6-bromo-1-isopropyl-1H-indole-3-carboxylic acid (2.0 g, 7.09 mmol). The reaction was stirred at 0° C. for 15 min and then was allowed to warm to 25° C. where it was stirred for 15 min. The reaction was then treated with 2-aminothiazole (1.63 g, 16.31 mmol) and stirred at 25° C. for 18 h. At this time, the mixture was partitioned between water (150 mL) and ethyl acetate (150 mL) and treated with a 1N aqueous hydrochloric acid solution (100 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL), water (1×100 mL), and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) afforded 6-bromo-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (300 mg, 11.6%) as white solid: mp 205-207° C.; EI-HRMS m/e calcd for C15H14BrN3OS (M+) 363.0041, found 363.0034.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:10][CH:9]2[O:21][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to the procedure described under (c), by alkylating tert-butyl (3RS,4RS)-4-(4-chlorophenyl)-3,4-dihydroxy-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-chlorophenyl)-4-hydroxy-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a light yellow oil; MS: 411, 41 3 [M-(C4H8)]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([CH3:13])[C:6]=2[C:14]=1[O:15][CH3:16].C(Cl)(=O)C(Cl)=O.[CH3:23][O:24][C:25](=[O:47])[C@@H:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH:27]([CH3:29])[CH3:28].N1C=CC=CC=1>ClCCl>[CH3:23][O:24][C:25](=[O:47])[C@@H:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:41]=[CH:42][C:43]([NH:46][C:10]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[C:14]([O:15][CH3:16])[C:6]=4[C:7]=3[CH3:13])=[O:12])=[CH:44][CH:45]=2)=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH:27]([CH3:29])[CH3:28]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Reactant: COc1c(Cl)ccc2oc(C(=O)O)c(C)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(Cl)c(OC)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To 80 mg (0.33 mmol) of 5-chloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 2 mL of oxalyl chloride and the mixture refluxed for 2 h, then stirred room temperature overnight. The excess oxalyl chloride was removed under vacuum. The residue was dissolved in 2 mL of dichloromethane and was added to a mixture of 181 mg (0.5 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester and 1 mL of pyridine in an ice/water bath. The mixture was stirred at 0° C. overnight. The reaction mixture was diluted with dichloromethane and was washed with 2N HCl, and water. Removal of the solvent in vacuo gave the crude product which was purified by column chromatography to give 168 mg (86% yield) of (S)-2-{4′-[(5-chloro-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:17]=3[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:17]=3[NH:16][CH:15]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccncc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2[nH]cc(C3CCNCC3)c2cn1
Yield: 158.1 %

Procedure:
4-(1H-Pyrrolo[3,2-c]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 6.6 mmol) was set stirring in 1:1 TFA/CH2Cl2. After 45 min the mixture was evaporated and the golden oil brought up in Et2O. A solid formed and was filtered, washed with Et2O and air dried to give 2.1 g (100%) of a white solid as a TFA salt. MS (electrospray): exact mass calculated for C12H15N3, 201.13. m/z found, 202.1 [M++H]. 1H NMR (CDCl3, 400 MHz): 9.4 (br s, 1H), 8.96 (s, 1H), 8.26 (d, J=5.87 Hz, 1H), 7.24 (s, 1H), 6.99 (s, 1H), 3.22-3.16 (m, 2H), 3.05-2.95 (m, 1H), 2.86-2.77 (m, 2H), 2.05 (d, J=12.72 Hz, 2H), 1.89 (br s, 1H), 1.75-1.63 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1)[CH3:2].[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[CH2:10][CH:11]([CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCc1ccc(C(=O)C=Cc2ccccc2)cc1
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc(CC)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(4-ethylphenyl)-3-phenylprop-2-en-1-one and diethyl malonate, diethyl 2-[3-(4-ethylphenyl)-3-oxo-1-phenylpropyl]malonate was obtained as colourless solid.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:30]=[CH:29][C:16]3/[C:17](=[CH:26]/[C:27]#[N:28])/[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH2:20][CH2:21][C:15]=3[CH:14]=2)[C:10]2[CH:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]=[C:34]([CH3:35])[C:9]=2[N:8]=1)=[O:4].[OH-].[Na+]>C(O)C>[C:3]([CH2:5][CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:30]=[CH:29][C:16]3/[C:17](=[CH:26]/[C:27]#[N:28])/[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH2:20][CH2:21][C:15]=3[CH:14]=2)[C:10]2[CH:31]=[C:32]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:33]=[C:34]([CH3:35])[C:9]=2[N:8]=1)([OH:4])=[O:2]
Reactant: COC(=O)CCc1nc2c(C)cc(-c3ccccc3)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-c2ccccc2)cc2c1nc(CCC(=O)O)n2Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
[step 1] (E)-{2-[2-(2-Methoxycarbonylethyl)-4-methyl-6-phenylbenzimidazol-1-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (350 mg, 0.65 mmol) obtained in Example 61, step 1 was dissolved in ethanol (4 mL), 2 mol/L aqueous sodium hydroxide solution (0.8 mL) was added, and the mixture was stirred at room temperature for 2 hr. The mixture was concentrated under reduced pressure, water and 2 mol/L hydrochloric acid were added, and the precipitate was collected by filtration to give (E)-[2-{2-(2-carboxyethyl)-4-methyl-6-phenylbenzimidazol-1-yl}methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (336 mg, 99%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([N:19]=O)[C:10]([CH3:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CCOC(C)=O>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:11]([NH2:19])[C:10]([CH3:21])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nn(Cc2ccccc2)c(-c2ccccc2)c1N=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nn(Cc2ccccc2)c(-c2ccccc2)c1N
Reaction time: 4 h

Procedure:
To a 0° C. solution of 2.32 g of 1-phenyl-butane-1,2,3-trione 2-oxime in 31 mL of EtOH was added a suspension of 2.43 g benzyl hydrazine dihydrochloride in 9 mL EtOH. The reaction mixture was warmed to rt and stirred for 96 h. The reaction mixture was concentrated under reduced pressure and purified by means of MPLC (120 g SiO2, 45% EtOAc:Heptane) to obtain 1-benzyl-3-methyl-4-nitroso-5-phenyl-1H-pyrazole. A suspension of 2.55 g 1-benzyl-3-methyl-4-nitroso-5-phenyl-1H-pyrazole, 34 mL EtOAc and 500 mg 10% Pd/C was reacted under 40 psi H2 atmosphere using a Parr apparatus. After 4 h, the suspension was filtered through Celite (EtOH eluting) and the filtrate was concentrated under reduced pressure and purified by means of MPLC (120 g SiO2, 60% EtOAc:Heptane) to give the title compound as an orange oil.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH2:7])(=[O:4])=[O:3].Cl[C:9]1[N:14]=[C:13]([C:15]2[S:19][C:18]([CH:20]([CH3:22])[CH3:21])=[N:17][C:16]=2[C:23]2[CH:24]=[CH:25][C:26]([F:41])=[C:27]([NH:29][S:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[F:40])(=[O:32])=[O:31])[CH:28]=2)[CH:12]=[CH:11][N:10]=1>C(O)(C)C>[F:40][C:34]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[S:30]([NH:29][C:27]1[CH:28]=[C:23]([C:16]2[N:17]=[C:18]([CH:20]([CH3:21])[CH3:22])[S:19][C:15]=2[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:14]=2)[CH:24]=[CH:25][C:26]=1[F:41])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)CCN
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3ccc(F)cc3F)c2)c(-c2ccnc(Cl)n2)s1
Solvent: CC(C)O
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3ccc(F)cc3F)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
[2-(Methylsulfonyl)ethyl]amine (352 mg, 2.86 mmol) and N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,4-difluorobenzenesulfonamide (150 mg, 0.286 mmol) were combined and heated to 55° C. overnight. Isopropanol (1 mL) was added to the reaction mixture and stirred an additional 30 min. The reaction mixture was cooled to rt and partitioned between DCM and 10% aqueous HCl. The organic layer was separated and dried over MgSO4, filtered, and concentrated over silica gel. The crude product was chromatographed on silica gel eluting with 100% DCM to 6:4 [DCM:(9:1 EtOAc:MeOH)]. The clean fractions were combined and concentrated to obtain the title compound as a white foam (82.1 mg; 45% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.65 (s, 1H) 8.14 (d, J=4.2 Hz, 1H) 7.72 (q, J=7.6 Hz, 1H) 7.54 (t, J=9.7 Hz, 1H) 7.47 (br. s., 1H) 7.30-7.42 (m, 2H) 7.11-7.30 (m, 2H) 6.23 (d, J=1.2 Hz, 1H) 3.64 (d, J=0.9 Hz, 2H) 3.20-3.40 (m, 2H range includes water peak) 2.99 (s, 3H) 1.33 (d, J=6.7 Hz, 6H). MS (ESI): 612.2 [M+H]+.
Reaction SMILES: N[C:2]1[C:7]2[O:8][CH2:9][CH2:10][C:11]3([S:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])[C:6]=2[CH:5]=[C:4]([F:18])[CH:3]=1.F[B-](F)(F)F.[H+].N([O-])=[O:26].[Na+]>O>[F:18][C:4]1[CH:3]=[C:2]([OH:26])[C:7]2[O:8][CH2:9][CH2:10][C:11]3([S:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])[C:6]=2[CH:5]=1
Reactant: O=N[O-]
Reactant: Nc1cc(F)cc2c1OCCC21SC(=O)NC1=O
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: O=C1NC(=O)C2(CCOc3c(O)cc(F)cc32)S1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
268 mg of (±)-8-amino-6-fluoro-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione were introduced into 3 ml of 50% tetrafluoroboric acid and the mixture was treated dropwise in an ice-bath with a solution of 76 mg of sodium nitrite in 0.3 ml of water. The mixture was subsequently stirred at room temperature for 90 minutes and then excess nitrite was destroyed by the addition of some urea. The solution of the diazonium salt was introduced in one portion into a solution of 12.08 g of copper (II) nitrate in 25 ml of water with vigorous stirring. After the addition of a small spatula tip of copper (I) oxide, vigorous gas evolution occurred. The mixture was stirred at room temperature until the foaming had finished (about 90 minutes). The product was thereupon extracted with three portions of ether, the organic phases were washed four times with water and dried with sodium sulfate. The residue remaining after removal of the solvent by concentration was separated by chromatography on preparative thick-layer plates and the (±)-6-fluoro-8-hydroxy-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione was isolated as a non-crystallizable, solid material.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Product: Cc1ccc(N)c(C(=O)NCCC[C@@H]2CN(c3ccc4c(c3)NC(=O)CS4)C(=O)O2)c1
Yield: 56 %

Procedure:
Starting from 2-amino-5-methylbenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (130 mg; 56% yield).
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].[NH2:8][C:9]1[N:10]=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:12][C:13]=1[C:14]([NH2:16])=[O:15].[OH-].[Na+].Cl>C(O)C.C(O)(=O)C>[CH3:1][C:2]1[NH:8][C:9]2[N:10]=[C:11]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[S:12][C:13]=2[C:14](=[O:15])[N:16]=1
Reactant: NC(=O)c1sc(N2CCOCC2)nc1N
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc(=O)c2sc(N3CCOCC3)nc2[nH]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
A mixture of acetic anhydride (4 ml, 42.4 mmol), Acetic Acid (2.00 ml) and 4-amino-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (200 mg, 0.876 mmol) was stirred at 60° C. for 3 h, then quenched with methanol and concentrated under reduced pressure. A mixture of the residue, Ethanol (2.000 ml) and 6N NaOH (2 ml, 12.00 mmol) was irradiated (uwave) at 120° C. for 30 min, then acidified with 6N HCl to pH ˜5. The precipitate was collected, rinsed with water, and dried under vacuum to furnish 5-methyl-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (175 mg, 79%). LC/MS: MS(ES+) m/e 253 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.31 (s, 3H) 3.54-3.59 (m, 4H) 3.69-3.75 (m, 4H) 12.34 (br. s., 1H).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([C:23]2[CH:24]=[CH:25][C:26]([CH2:32][CH3:33])=[C:27](B(O)O)[CH:28]=2)=[CH:21][CH:20]=1>>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([C:23]2[CH:24]=[CH:25][C:26]([CH2:32][CH3:33])=[C:27]([Pb+3:17])[CH:28]=2)=[CH:21][CH:20]=1
Reactant: [Pb+4]
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1B(O)O
Agent: CC(=O)[O-]
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Temperature: 40 °C
Yield: 100 %

Procedure:
To a mixture of lead tetraacetate (2.15 g, 4.85 mmol) and mercuric diacetate (0.15 g, 0.47 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (6 ml). This mixture is warmed to 40° C., and 4′-chloro-4-ethylbiphen-3-ylboronic acid (1.17 g, 4.50 mmol) is added in one portion and the suspension is heated at this temperature for 5 hours. The mixture is than cooled to room temperature, concentrated to a small volume and triturated with hexanes and filtered to yield crude 4′-chloro-4-ethylbiphen-3-yllead triacetate (2.70 g).
Reaction SMILES: [CH2:1]([N:8]([C:19](=[O:24])[C:20](Br)([CH3:22])[CH3:21])[C:9]1[CH:14]=[C:13]([O:15]CC)[CH:12]=[CH:11][C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[CH2:1]([N:8]1[C:9]2[C:14](=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=2[CH3:18])[C:20]([CH3:21])([CH3:22])[C:19]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(C)c(N(Cc2ccccc2)C(=O)C(C)(C)Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cc1ccc(O)c2c1N(Cc1ccccc1)C(=O)C2(C)C
Temperature: 125 °C
Reaction time: 0.47 h

Procedure:
31.2 g (80.0 mmol) of N-benzyl-2-bromo-5'-ethoxy-2'-methylisobutyranilide was dissolved in 258 ml of chlorobenzene. After the addition of 53.2 g (399 mmol) of aluminum chloride powder, the mixture was heated while stirring for 28 minutes at 125° C. The resulting mixture was cooled, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, 3:1 mixture of n-hexane and ethyl acetate) and recrystallized (ether-n-hexane) to obtain 9.06 g (yield, 40.3%) of colorless prisms of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>CO.Cl.O=[Pt]=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Clc1cc(Cl)cc(-c2cccnc2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: Clc1cc(Cl)cc(C2CCCNC2)c1
Yield: 196.8 %

Procedure:
Synthesized according to General Procedure 37. A solution of 3-(3,5-dichlorophenyl)-pyridine (481 mg, 2.15 mmol) in MeOH (4.6 mL) and 2 M HCl (0.6 mL) was stirred under 60 psi of H2 in the presence of PtO2 (283 mg, 1.246 mmol) for 3 h using a Parr shaker. The reaction mixture was filtrated through Celite, and the filter cake was washed thoroughly with MeOH. The filtrate was concentrated under reduced pressure to afford 3-(3,5-dichlorophenyl)piperidine hydrochloride (564 mg, 92%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=230.3; tR=1.14 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=2[CH:11]=[C:12]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH:13]=1)=[O:4].O[Li].O>C1COCC1.O>[CH3:19][N:17]([CH3:18])[CH2:16][CH2:15][O:14][C:12]1[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]2[CH:7]=[CH:8][N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=2[CH:11]=1
Reactant: COC(=O)c1cc(OCCN(C)C)cc2c1ccn2C(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1ccc2c(C(=O)O)cc(OCCN(C)C)cc21
Yield: 84 %

Procedure:
To a solution of 6-(2-dimethylamino-ethoxy)-1-isopropyl-1H-indole-4-carboxylic acid methyl ester (500 mg, 1.64 mmol) in THF (5 mL) was added LiOH.H2O (200 mg, 4.93 mmol) in water (5 mL). the reaction was heated at reflux for 5 h, at which time the THF was removed under reduced pressure. The remaining mixture was acidified with 1 N HCl (pH˜6) and extracted with 10% MeOH in chloroform (4×30 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated to yield 6-(2-dimethylamino-ethoxy)-1-isopropyl-1H-indole-4-carboxylic acid (400 mg), which was used in the next stage without further purification. LCMS (ES+): m/z=291.30 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[CH3:35][N:36]([CH3:46])[C:37](=[O:45])[CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:42]3[CH2:41][CH2:40][N:39]([CH2:38][C:37]([N:36]([CH3:46])[CH3:35])=[O:45])[CH2:44][CH2:43]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:33])[CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: COc1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Product: COc1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(=O)N(C)C)CC2)c(OC(C)C)c1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 6) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Chemicals) in an analogous manner as described in example 8. LR-MS: 652.3 [(M+H)+].
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.[O:19]=[S:20]1(=[O:27])[CH2:25][CH2:24][N:23]([NH2:26])[CH2:22][CH2:21]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([CH:12]=2)[C:9]([NH:26][N:23]2[CH2:24][CH2:25][S:20](=[O:27])(=[O:19])[CH2:21][CH2:22]2)=[O:11])[CH2:2][CH2:3]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CC2)c1
Reactant: NN1CCS(=O)(=O)CC1
Product: O=C(NN1CCS(=O)(=O)CC1)c1cnc(OCC(F)(F)F)c(C2CC2)c1

Procedure:
The title compound was synthesized in analogy to the procedure described in Example 34 c), using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (example 34b) and 1,1-dioxo-1λ6-thiomorpholin-4-ylamine as starting materials (CAN 26494-76-8); MS (ESI) 394.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.C1C(=O)N([I:21])C(=O)C1.[OH-].[Na+]>OS(O)(=O)=O>[I:21][C:12]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:13])[NH:9][CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)C(=O)NCC2
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1I)C(=O)NCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.2 %

Procedure:
To a mixture of 7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (53a, 1.7 g, 9.6 mmol) in conc. H2SO4 (40 mL) was added portionwise NIS (2.4 g, 11 mmol) at 0° C. The mixture was stirred at room temperature for 14 hours. The mixture was chilled to 0° C. and basified with aq. NaOH to pH 8. The mixture was extracted with EtOAc (5×60 mL). The combined organic layers were washed with brine (3×60 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 1:1) to give 8-iodo-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (53b, 2.1 g, 79%) as a yellow solid.