Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[N:15][CH:16]=2)[O:6][C:7]=1[CH2:8][O:9][CH3:10].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH:19]1([CH:2]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:3]2[CH:4]=[C:5]([C:11]3[CH:16]=[N:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[O:6][C:7]=2[CH2:8][O:9][CH3:10])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COCc1oc(-c2ccc(OC)nc2)cc1C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCc1oc(-c2ccc(OC)nc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
A mixture of 5-{4-[chloro(cyclohexyl)methyl]-5-(methoxymethyl)furan-2-yl}-2-methoxypyridine (0.4 g), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.4 g), sodium carbonate (0.2 g) and sodium iodide (0.2 g) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 70% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.45 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (91 mg, 14%).
Reaction SMILES: Br[CH:2]([CH:5]=[O:6])[CH:3]=O.[Br:7][C:8]1[C:9]([CH3:15])=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(#N)C>>[Br:7][C:8]1[C:9]([CH3:15])=[CH:10][C:11]2[N:12]([C:2]([CH:5]=[O:6])=[CH:3][N:14]=2)[CH:13]=1
Reactant: O=CC(Br)C=O
Reactant: Cc1cc(N)ncc1Br
Solvent: CC#N
Product: Cc1cc2ncc(C=O)n2cc1Br
Yield: 79.81 %

Procedure:
Bromomalonaldehyde (5000 mg, 26.74 mmol) was added to a solution of 5-bromo-4-methylpyridin-2-amine in acetonitrile (5250 mg, 34.76 mmol). The reaction mixture was refluxed for 2 hours. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated in vacuum and the product was purified by column chromatography using ethyl acetate-petroleum ether gradient to obtain the title compound. Yield: 79.81%; 1H NMR (DMSO-d6; 300 MHz): δ 9.90 (s, 1H), 9.52 (s, 1H), 8.51 (s, 1H), 7.94 (s, 1H), 2.50 (s, 3H); MS (m/z): 239 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](=O)[NH:12][CH:11]=[N:10][C:9]=3[S:15][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:18]>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13]([Cl:18])=[N:12][CH:11]=[N:10][C:9]=3[S:15][C:4]=2[CH:3]=1
Reactant: O=c1[nH]cnc2sc3cc(Br)ccc3c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Clc1ncnc2sc3cc(Br)ccc3c12
Yield: 91 %

Procedure:
7-Bromo[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (7.80 g, 27.7 mmol), POCl3 (70 mL) and triethylamine (70 mL) were heated in an oil bath at 80° C. for 3 h. The resulting slurry was concentrated on a rotavap, slurried in dichloromethane and poured into 500 mL of satd NaHCO3. The organic phase was then washed with satd NaHCO3, water, and then collected. The initial aqueous phase (pH<1) was basified with 1.0 N NaOH and extracted with dichloromethane. The organic layers were combined, dried with sodium sulfate, filtered, and concentrated under high vacuum to yield a crude brown solid (7.6 g, 91%). 1H NMR (DMSO-d6) δ 9.05 (s, 1H), 8.60 (d, 1H), 8.60 (s, 1H), 7.88 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:19])[C:15]([O:17]C)=[O:16])=[CH:10][C:9]=2[CH3:20])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:27]([O:36]C(OC(C)(C)C)=O)[C:26]([C:44]([F:47])([F:46])[F:45])=[CH:25][CH:24]=1>>[C:32]([O:31][C:29]([C:28]1[C:27]([OH:36])=[C:26]([C:44]([F:46])([F:47])[F:45])[CH:25]=[CH:24][C:23]=1[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:19])[C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH3:20])=[CH:6][CH:7]=1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: COC(=O)C(C)c1ccc(-c2ccc(O)cc2)c(C)c1
Product: Cc1cc(C(C)C(=O)O)ccc1-c1ccc(OCc2ccc(C(F)(F)F)c(O)c2C(=O)OC(C)(C)C)cc1
Yield: 53 %

Procedure:
According to a method similar to Example (2-3), Example (33-5) and Example (17-4), from methyl 2-(4′-hydroxy-2-methyl-1,1′-biphenyl-4-yl)propanoate (224 mg, 0.83 mmol) obtained in Example (107-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (415 mg, 0.91 mmol) obtained in Example (28-5), the title compound was obtained as a colorless powder (235 mg, three-step total yield: 53%).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][S:5][C:4](=[O:7])[CH:3]=1.COC1C=C2C(=C(OC)C=1)N(CC1C=CC(Cl)=CC=1)C=C2.C(=O)([O-])[O-].[K+].[K+].[Cl:35][C:36]1[CH:56]=[CH:55][C:39]([CH2:40][N:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]([C:50](=[O:54])[C:51](Cl)=[O:52])=[CH:42]2)=[CH:38][CH:37]=1>COCCOC.O>[Cl:35][C:36]1[CH:56]=[CH:55][C:39]([CH2:40][N:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]([C:50](=[O:54])[C:51]([NH:1][C:2]3[CH2:6][S:5][C:4](=[O:7])[CH:3]=3)=[O:52])=[CH:42]2)=[CH:38][CH:37]=1
Reactant: O=C(Cl)C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Reactant: NC1=CC(=O)SC1
Agent: COc1cc(OC)c2c(ccn2Cc2ccc(Cl)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=C1C=C(NC(=O)C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)CS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 4-amino-5H-thiophen-2-one of Preparation 5 (103 mg), powdered potassium carbonate (138 mg) and 2-(1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride of Example 1 (334 mg) in 1,2-dimethoxyethane (5 ml) is stirred at room temperature for 2 h. After this time the reaction mixture is poured in water (50 ml) and the obtained precipitate is collected by filtration and thoroughly washed with water. The still wet solid is suspended in methanol and stirred for 30′. Filtration followed by drying at 40° C. under vacuum gives 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-(5-oxo-2,5-dihydro-3-thienyl)acetamide (280 mg).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[CH3:9][Mg+].[Br-]>C1COCC1.CCOCC>[Cl:1][C:2]1[S:3][C:4]([C:7](=[O:8])[CH3:9])=[CH:5][N:6]=1
Reactant: O=Cc1cnc(Cl)s1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1cnc(Cl)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
2-Chloro-thiazole-5-carbaldehyde (1.00 g., 6.77 mmol) was dissolved in THF (10 mL) and cooled to −78° C. MeMgBr (2.26 mL of a 3.0 M solution in Et2O, 6.78 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min and then allowed to slowly warm to −20° C. over a further 30 min. The reaction was quenched by the addition of EtOAc (2 mL), allowed to warm to 20° C., and 2 M hydrochloric acid (20 mL) was added. The mixture was poured into water (200 mL) and extracted into DCM (200 mL), dried (Na2SO4) and concentrated. The residue was dissolved in reagent grade acetone (20 mL), cooled in an ice bath, and Jones' reagent (3.0 mL of a 2.67 M solution) was added dropwise. The mixture was stirred for 16 h, allowing to warm to 20° C., and then quenched with IPA (5 mL), poured into saturated aqueous NaHCO3 (200 mL) and extracted with EtOAc (2×100 mL). The EtOAc extracts were dried (Na2SO4) and concentrated to give pure product (800 mg, 73%) as a somewhat volatile white solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])(OCC)=O)C.[CH2:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[C:24]([O:36][CH2:37][O:38][CH3:39])=[C:25]([O:34][CH3:35])[CH:26]=[C:27]2[CH:32]=O)[CH3:21].O>CN(C)C=O>[CH2:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[C:24]([O:36][CH2:37][O:38][CH3:39])=[C:25]([O:34][CH3:35])[CH:26]=[C:27]2/[CH:32]=[CH:11]/[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13])[CH3:21]
Reactant: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Reactant: CCOP(=O)(CC(=O)N1CCCCC1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cccc2c(/C=C/C(=O)N3CCCCC3)cc(OC)c(OCOC)c12
Reaction time: 0.17 h
Yield: 98.4 %

Procedure:
0.15 g of 60% sodium hydride was suspended in 20 ml of N,N-dimethylformamide, to which 1.15 g of N-(diethoxyphosphoryl)acetylpiperidine was gradually added at room temperature. After stirring for 10 minutes, a solution of 800 mg of 5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde in N,N-dimethylformamide (10 ml) was gradually added. After stirring for 20 minutes, water was added, followed by extraction with ethyl acetate. The combined extracts were washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the resultant residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to obtain 1.1 g of the titled compound as pale yellow crystals.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:35]=[CH:34][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:20])=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>CC(O)C>[N:28]1([C:24]2[CH:23]=[C:22]([NH:21][C:19]([C:18]3[CH:34]=[C:35]([C:2]4[CH:7]=[CH:6][C:5]([C:8]5[O:9][C:10]([CH3:13])=[N:11][N:12]=5)=[CH:4][CH:3]=4)[C:15]([CH3:14])=[CH:16][CH:17]=3)=[O:20])[CH:27]=[CH:26][CH:25]=2)[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: Cc1nnc(-c2ccc(I)cc2)o1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Solvent: CC(C)O
Product: Cc1nnc(-c2ccc(-c3cc(C(=O)Nc4cccc(N5CCOCC5)c4)ccc3C)cc2)o1

Procedure:
Example 36 was prepared using 2-(4-iodophenyl)-5-methyl-[1,3,4]oxadiazole (Intermediate 15) and 4-methyl-N-(3-morpholin-4-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 5) with propan-2-ol as the solvent.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[C:4]([NH2:21])[N:3]=1.[C:22]([C:24]1[CH:25]=[C:26]([CH2:30]O)[CH:27]=[CH:28][CH:29]=1)#[CH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:22]([C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:30][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:10]2[CH:9]=[C:8]([C:7]3[C:2]([NH2:1])=[N:3][C:4]([NH2:21])=[CH:5][CH:6]=3)[O:12][N:11]=2)=[CH:15][CH:16]=1)#[CH:23]
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Reactant: C#Cc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#Cc1cccc(COc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
To a tetrahydrofuran (10 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (150 mg, 0.53 mmol) described in Manufacturing Example 18-1-1, (3-ethynyl-phenyl)-methanol (91 mg, 0.69 mmol) described in Manufacturing Example 214-1-2, and triphenylphosphine (180 mg, 0.69 mmol) was added diethyl azodicarboxylate (300 mg, 0.69 mmol, 40% toluene solution), which was stirred for 30 minutes at room temperature. NH silica gel was added to the reaction solution, and the solvent was evaporated under a reduced pressure. The crude product that had adsorbed to the NH silica gel was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1, then 1:1, then ethyl acetate) to obtain the title compound (110 mg, 51%).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[O:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1.O>[O:26]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1ccccc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(COc2ccc(-c3ccccc3Oc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A degassed solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Inter-mediate 1; 74 mg, 0.2 mmol) in dioxane (4 mL) and a degassed solution of potassium carbonate (83 mg) in water (0.4 mL) were added to a reaction vial containing (2-phenoxy)phenylboronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.; 128 mg, 0.6 mmol). The solution was degassed and bis(tri-cyclohexylphos-phine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 7 mg, 0.01 mmol) was added. The mixture was heated in a microwave oven at 170 degrees for 25 min. The reaction mixture was filtered through silica, and washed with dioxane (1 mL) and dimethylacetamide (1 mL). 2 M potassium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight, and then 1 M HCl (0.8 mL) was added. The solvent was evaporated and the residue was triurated with 50% aqueous methanol to give 3-(2′-phenoxy-biphenyl-4-yloxymethyl)-benzoic acid. Mass spectrum MH+=397.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][C:10]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]2[C:11]=1[C:12]([CH3:22])([CH3:21])[CH2:13][CH2:14][S:15]2>C(Cl)Cl>[C:5]([C:19]1[C:10]([Cl:9])=[C:11]2[C:16](=[C:17]([Cl:20])[CH:18]=1)[S:15][CH2:14][CH2:13][C:12]2([CH3:22])[CH3:21])(=[O:7])[CH3:6]
Reactant: CC1(C)CCSc2c(Cl)ccc(Cl)c21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2c(c1Cl)C(C)(C)CCS2
Temperature: 0 °C
Yield: 55.7 %

Procedure:
1.26 Grams (9.45 mmol) of anhydrous aluminum chloride was suspended in 10 ml of methylene chloride, and a solution of 0.74 g (9.45 mmol) of acetyl chloride in 5 ml of methylene chloride was dropwise added with cooling with ice. The mixture was stirred until the reaction mixture was homogeneous, then, a solution of 1.95 g (7.88 mmol) of 5,8-dichloro-4,4-dimethylthiochroman in 5 ml of methylene chloride was added, and the mixture was allowed to react at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was poured into ice water and extracted with methylenechloride. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The methylene chloride was distilled off under reduced pressure, and the resultant oily substance was purified by silica gel column chromatography to give 1.27 g (yield 56%) of 6-acetyl-5,8-dichloro-4,4-dimethylthiochroman.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]([O-])(=O)[CH3:13].[Na+]>[Cu].CC1C=CC=CC=1>[I:1][C:2]1[CH:10]=[C:6]([C:7]([NH:9][C:6]2[CH:10]=[CH:2][CH:3]=[CH:4][C:12]=2[CH3:13])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: NC(=O)c1cc(I)ccc1O
Agent: [Cu]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1NC(=O)c1cc(I)ccc1O

Procedure:
37.1 g. of 5-iodo salicylamide, 43.6 g. of 2-methyl benzene, 10 g. of anhydrous sodium acetate, 1 g. of copper bronze are mixed together and heated under reflux for 4 hours. The molten mass obtained is dissolved in alcohol. Said solution is filtered and concentrated by evaporation. 5-iodo-2'-methyl salicylanilide is obtained thereby. Said compound is then dissolved in about 5 times its amount by weight of a mixture of glacial acetic acid and ethyl acetate (1:1). A solution of 40.8 g. of bromine in 30 cc. of glacial acetic acid is added to said solution to obtain 5-iodo-2'-methyl-4'-bromo salicylanilide. Resulting compound (compound No. 5) forms colorless needle-shaped crystals having properties shown in Table 5 by recrystallizing from ethanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH2:23]([CH:25]([CH2:28][CH3:29])[CH:26]=[O:27])[CH3:24].[NH4+].[Cl-]>C1COCC1>[S:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH:26]([CH:25]([CH2:28][CH3:29])[CH2:23][CH3:24])[OH:27])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: CCC(C=O)CC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)C(O)c1ccc(Nc2nc3ccccc3s2)cc1
Temperature: -70 °C
Yield: 67.9 %

Procedure:
The following reaction was performed under a N2 atmosphere. A mixture of N-(4-bromophenyl)-2-benzothiazolamine (0.492 mol) in THF (2700 ml) was stirred at −70° C. Butyllithium (0.984 mol; 2.5 M in hexane) was added dropwise at −65° C. The mixture was stirred for one hour. A solution of 2-ethyl-butanal (0.492 mol) in THF (300 ml) was added dropwise at −75° C. The mixture was allowed to warm to RT overnight. A 10% aqueous NH4Cl solution (3000 ml) was added and the mixture was stirred for 15 minutes The separated aqueous phase was extracted with EtOAc (1000 ml). The separated organic layer was dried, filtered and the solvent evaporated. The residue was crystallized from methyl isobutyl keton. The precipitate was filtered off and dried, yielding 109 g (68%) of (±)-4-(2-benzothiazolylamino)-α-(1-ethyl-propyl)benzenemethanol (interm 28).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([F:28])[C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f41) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15]>Cl.C1C=CC=CC=1>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: C1=COCCC1
Reactant: N#CCCCCCCO
Agent: Cl
Solvent: c1ccccc1
Product: N#CCCCCCCOC1CCCCO1
Yield: 87.1 %

Procedure:
3,4-Dihydro-2H-pyran (272 g.) was added dropwise at 40° C. with stirring to a mixture of 7-hydroxyheptanenitrile (284 g.) and concentrated hydrochloric acid (10 drops). The temperature was allowed to rise to 65° C. and was maintained at this level for one hour. The solution was cooled and benzene (500 ml.) was added. The solution was washed with aqueous sodium bicarbonate and then water, and dried over sodium sulphate. The solvent was removed in vacuo, and the residue distilled under reduced pressure to give 7-(2-tetrahydropyranyloxy)heptanenitrile (411 g.), b.p. 100°-130° C./0.1 mm.Hg, nD25 1.455.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]1=[O:23].Br[CH2:25]/[CH:26]=[CH:27]/[C:28]([O:30][CH3:31])=[O:29].C(=O)(O)[O-].[Na+]>CO>[Cl:9][C:6]1[C:7]2[O:8][CH:26]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:25][NH:1][C:2]=2[C:3]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:4]([F:10])[CH:5]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Reactant: COC(=O)/C=C/CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC1CNc2c(c(Cl)cc(F)c2-n2c(=O)cc(C(F)(F)F)n(C)c2=O)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.7 %

Procedure:
A mixture of 3-(2-amino-4-chloro-6-fluoro-3-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (0.43 g), methyl 4-bromocrotonate (0.22 g ) and sodium bicarbonate (0.3 g ) in methanol was stirred at 25° C. for 12 hours . The solvent was removed under reduced pressure and ethyl acetate (200 ml) was added. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to an oil. The crude product was purified by column chromatography on silica gel using ethyl acetate-hexane (1:2) as eluent to give title compounds (0.097 g)
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.O>CS(C)=O>[F:27][C:28]([F:37])([F:38])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: CS(C)=O
Solvent: O
Product: O=C1Cc2c(ccc3c2OC(CNCc2ccc(C(F)(F)F)cc2)CO3)N1
Temperature: 85 °C
Yield: 53.8 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.03 g, 2.75 mmole) and 4-trifluoromethylbenzylamine (1.60 ml, 11.2 mmole) were combined in 15 ml of dry DMSO and heated to 85° C. for 3.5 hours under a nitrogen atmosphere. After cooling to room temperature, 150 ml of water was added and the mixture was extracted twice with 250 ml portions of 35% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 5% methanol/CH2Cl2 as eluant. The free base of the title compound (0.56 g, 54%) thus obtained was crystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.06 g of the (S) enantiomer of the title compound as an off-white solid fumarate, m.p. 211-212° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12](OCC)=[O:13])=[CH:4][C:3]=1[Cl:17].O.[NH2:19][NH2:20]>C(O)C>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([NH:19][NH2:20])=[O:13])=[CH:4][C:3]=1[Cl:17]
Reactant: NN
Reactant: CCOC(=O)c1cc(Cl)c(N)c2c1OCCO2
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cc(Cl)c(N)c2c1OCCO2

Procedure:
38.4 g (0.149 mol) of ethyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylate suspended in 150 ml of ethanol are introduced into a 1 l reactor, 149 g (2.98 mol) of hydrazine hydrate are added, over 15 min, and the mixture is refluxed for 1 h.