Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[F:19])[CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:51]=[CH:50][CH:49]=[C:48]([F:52])[C:22]=1[CH2:23][CH2:24][C@H:25]1[O:30][CH2:29][C@@H:28]([CH2:31][O:32][C:33](=[O:40])[NH:34][CH2:35][C:36]([F:39])([F:38])[F:37])[N:27](C(OC(C)(C)C)=O)[CH2:26]1>>[F:39][C:36]([F:37])([F:38])[CH2:35][NH:34][C:33](=[O:40])[O:32][CH2:31][C@@H:28]1[CH2:29][O:30][C@H:25]([CH2:24][CH2:23][C:22]2[C:21]([NH:20][C:10](=[O:12])[CH2:9][C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[F:19])=[CH:51][CH:50]=[CH:49][C:48]=2[F:52])[CH2:26][NH:27]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: O=C(O)C[C@@H](c1ccc(F)cc1)c1ccncc1F
Product: O=C(C[C@@H](c1ccc(F)cc1)c1ccncc1F)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 8 and 9 of Example 89. MS (ES) m/z=625.5 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([C:4]#[CH:5])[OH:3].P(=O)(O)(O)O.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(OC(=O)C)(=O)C.CO>[C:12]([O:3][C:2]([CH3:6])([CH3:1])[C:4]#[CH:5])(=[O:14])[CH3:13]
Reactant: C#CC(C)(C)O
Reactant: CC(=O)OC(C)=O
Agent: O=P(O)(O)O
Solvent: CO
Product: C#CC(C)(C)OC(C)=O
Reaction time: 8 h

Procedure:
112 g (one mole) of freshly distilled dimethylethynyl carbinol is treated with 1.2 moles of acetic anhydride containing 10 drops of 85% phosphoric acid. The acetic anhydride is added to the carbinol dropwise with shaking while maintaining the temperature under 40°. The mixture is allowed to stand overnight, washed with two 75 ml portions of cold water, and the water washings are extracted with ether. The ether extract is added to the main portion of ester and the combined ethereal solution is washed with 10% sodium carbonate solution until the washings remain basic to litmus. The solution is washed with two 75 ml portions of ice-water, dried over calcium chloride, and distilled to give the title compound.
Reaction SMILES: Cl[CH:2]([C:6](=O)[CH3:7])[CH2:3][C:4]#[N:5].[NH2:9][C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=[CH:12][N:11]=1.C(N(CC)CC)C>C(O)C>[CH2:17]([O:16][C:15]1[C:10]2[N:11]([C:2]([CH2:3][C:4]#[N:5])=[C:6]([CH3:7])[N:9]=2)[CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: CC(=O)C(Cl)CC#N
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc2c(OCc3ccccc3)cccn2c1CC#N

Procedure:
A solution of 0.86 g. of 3-chloro-4-oxopentanonitrile, 0.92 g. of 2-amino-3-phenylmethoxypyridine and 0.5 ml. of triethylamine in 15 ml. of ethanol was stirred for 16 hours, then concentrated to remove the triethylamine and ethanol. The residue was dissolved in methylene chlorideand washed with water. The methylene chloride was concentrated and the residual oil was dissolved in 20 ml. of boiling acetonitrile, filtered, cooled, and treated with hydrogen chloride/methanol with cooling to give 0.22 g. of the desired product (m.p. 163°-166° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[I:9]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([I:9])=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(Cl)ccn1
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(I)cn1
Temperature: 80 °C
Yield: 66.8 %

Procedure:
4-Chloropyridin-2-amine (0.142 g, 1.10 mmol) and N-iodosuccinimide (0.273 g, 1.22 mmol) were combined in 1.5 mL of acetic acid. The solution was sonicated briefly and then heated to 80° C. After 1 hour the solution was cooled to room temperature and then concentrated under vacuum. After adjusting the pH to ˜8/9 with aqueous ammonia, a light brown solid was collected by filtration. The solid was purified on a 12 g Combiflash column eluting with a gradient of DCM to 5% methanol/0.25% NH4OH (˜28% in water)/DCM. The fractions containing the product were combined and concentrated under vacuum to give 4-chloro-5-iodopyridin-2-amine (187 mg, 67%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.20 (1 H, s), 6.69 (1 H, s), 6.40 (2 H, s); LCMS-ESI (POS), M/Z, M+1: Found 254.9.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:32][CH2:33][C@H:34]([NH:40][S:41]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=[O:43])=[O:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CCOC(C)=O>[CH2:38]([O:37][C:35](=[O:36])[C@@H:34]([NH:40][S:41]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=[O:42])=[O:43])[CH2:33][NH:32][C:13](=[O:15])[CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:39]
Reactant: CCOC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CNC(=O)CNC(=O)OCc1ccccc1)NS(=O)(=O)c1ccccc1
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
N-Cbz-glycine (339 mg, 1.62 mmol) was dissolved in 8 mL EtOAc, cooled to -15° C., then NMM (196 μL, 1.8 mmol) and isobutyl chloroformate (230 μL, 1.8 mmol) were added. After 20 min, the mixed anhydride solution was added to amine 3-4 (0.50 mg, 1.6 mmol) suspended in 5 niL EtOAc and the reaction was warmed to RT for 90 min. Following dilution with EtOAc, the mixture was washed with water, sat. NaHCO3, 5% KHSO4, and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, 75% EtOAc/hexane) provided amide 3-5 as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH2:10][C:9](=O)[C:8]=2[C:7]([CH3:22])=[CH:6]1)(=[O:4])=[O:3].[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].[ClH:28].Cl.O>C(O)C>[ClH:28].[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][C:13]2[N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]([CH3:22])[C:8]=2[C:9](=[N:27][NH:26][C:23]([NH2:25])=[NH:24])[CH2:10]1
Reactant: Cc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1ccccc1F)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cn(S(C)(=O)=O)c2c1C(=NNC(=N)N)CC(c1ccccc1F)C2
Yield: 51.8 %

Procedure:
A mixture of 1-methanesulfonyl-3-methyl-6-(2-fluorophenyl)-4,5,6,7-tetrahydroindol-4-one (0.30 g), aminoguanidine hydrochloride (0.11 g), concentrated hydrochloric acid (0.047 ml), water (0.047 ml) and ethanol (30 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 6-(2-fluorophenyl)-4-guanidinoimino-1-methanesulfonyl-3-methyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 16) (0.2 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.[N:25]1([S:31]([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([S:31]([C:34]2[CH:35]=[C:36]([NH:40][C:22]([C:21]3[CH:20]=[N:19][N:12]4[C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)=[N:10][C:11]=34)=[O:24])[CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: COc1ccc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)cc1
Product: COc1ccc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)N5CCOCC5)c4)c3n2)cc1

Procedure:
The title compound was prepared from 5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [CAS 333761-72-1; commercially available] and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 562.4 [(M+H)+]; mp 203° C.
Reaction SMILES: [C:1]([N:11]1[CH2:19][CH:18]([OH:20])[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].N1C=CC=CC=1.[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>CO>[C:1]([N:11]1[CH2:19][CH:18]([O:20][S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COC(=O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1CC(OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
A stirred solution of 14.5 g. (0.052 mole) of N-carbobenzyloxy-4-hydroxy-L-proline, methyl ester in 30 ml. of pyridine is treated dropwise at -5° to -8° with a solution of 11 g. (0.058 mole) of tosyl chloride in 15 ml. of pyridine. The pale yellow solution is stored in the cold for 3 days, then added with stirring to 300 ml. of ice-cold 2 N hydrochloric acid. The precipitated gum is extracted with 200 ml. of chloroform. The aqueous phase is extracted with additional chloroform (3×100 ml.). The organic layers are combined, dried (MgSO4), and the solvent evaporated to give a pale yellow viscous oil. The oil is dissolved in 100 ml. of methanol and diluted to 400 ml. with water to precipitate the product as an oil which gradually crystallizes on seeding, rubbing, and cooling: yield 17.4 g. (77%); m.p. 62°-65°. Following crystallization from 85 ml. of isopropanol, the colorless solid N-carbobenzyloxy-4-tosyloxy-L-proline, methyl ester weighs 15.9 g. (70%); m.p. 67°-69°; [α]D26 -30° (c=1; methanol).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)OCC>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:6]2[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:2]([CH3:1])[CH2:7]2)=[CH:17][CH:18]=1)#[N:21]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2ccc(C#N)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 29.9 %

Procedure:
(S)-tert-butyl 2-methylpiperazine-1-carboxylate (1 g, 4.99 mmol), 4-fluorobenzonitrile (0.605 g, 4.99 mmol), and K2CO3 (0.897 g, 6.49 mmol) were combined into a vial equipped with a stir bar. The reaction was heated to 110° C. for 48 h. Cooled to RT, diluted with EA and filtered. Concentrated to a clear oil and purified on silica gel (80 g, 10-20% EA in Hex) to give a clear oil (450 mg, 30% yield) which became a crystalline solid upon sitting. [M+H] calc'd for C17H23N3O2, 301; found, 301.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([OH:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH3:32])[C:18]([C:24]1[CH:25]=[CH:26][C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1)([OH:23])[C:19]([F:22])([F:21])[F:20].[CH2:33]([O:35][C:36](=[O:39])[CH2:37]Br)[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:33]([O:35][C:36](=[O:39])[CH2:37][O:16][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:17]([CH3:32])[C:18]([OH:23])([C:24]3[CH:25]=[CH:26][C:27](=[O:31])[N:28]([CH3:30])[CH:29]=3)[C:19]([F:22])([F:20])[F:21])=[C:2]([Cl:1])[CH:7]=2)[CH:14]=[CH:13][C:12]=1[F:15])[CH3:34]
Reactant: CC(c1ccc(Oc2ccc(F)c(O)c2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)COc1cc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 147, step 6, 5-{2-[2-chloro-4-(4-fluoro-3-hydroxy-phenoxy)-phenyl]-1-hydroxy-1-trifluoromethyl-propyl}-1-methyl-1H-pyridin-2-one was reacted with ethylbromoacetate and cesium carbonate to give the title compound as a colorless solid. MS (m/e)=558.2 [M+H+].
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(C(=O)OC2CCN(C)C(=O)N2c2nnc(C3CC3)s2)cc1

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 4-Methoxybenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(4-methoxybenzoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[C:34]=1[OH:42].[CH2:43]([O:50][C:51](=[O:63])[C@@H:52]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:53]O)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[CH2:43]([O:50][C:51](=[O:63])[C@@H:52]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:53][O:42][C:34]1[C:35]([N+:39]([O-:41])=[O:40])=[CH:36][CH:37]=[CH:38][C:33]=1[Cl:32])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1cccc(Cl)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](COc1c(Cl)cccc1[N+](=O)[O-])C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50.9 %

Procedure:
Under an inert atmosphere, a solution of 6.5 g (25 mmol) of triphenylphosphine in 20 ml of tetrahydrofurane was treated with at 0° C. with 3.9 ml (25 mmol) of diethyl azodicarboxylate. Thereupon, 3.0 g (17 mmol) of 2-chloro-6-nitrophenol were added and the reaction mixture was stirred at 0° C. for 15 minutes. Finally, 4.93 g (17 mmol) of (S)-2-tert-butoxycarbonylamino-3-hydroxy-propionic acid benzyl ester were added and the reaction mixture was left to warm to room temperature. After stirring for 18 hours, for the working-up the solvent was evaporated under reduced pressure and the residue triturated in ether at 0° C. The precipitated triphenylphosphinoxide was filtered and washed with ether. The combined filtrates were evaporated to yield 12.8 g of the crude product as a brown-yellow oil. The crude product was purified by chromatography on silica gel using heptane and ethyl acetate as the eluent. There were obtained 3.9 g (50%) of the title compound as a yellow oil, [α]589=−5.96° (c=1.0% in MeOH), MS m/e (%): 468.1 (M+NH4+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cnn2c(-c3cccc(F)c3)ccnc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)c1cnn2c1NCC=C2c1cccc(F)c1
Reaction time: 16 h

Procedure:
A 136.3 g amount of 7-(3-fluorophenyl)-pyrazolo(1,5-a)pyrimidine-3-carboxamide (prepared as described in Example 7) in one liter of glacial acetic acid is stirred at room temperature, then 83.6 g of sodium cyanoborohydride is added portionwise under nitrogen. The mixture is stirred for 16 hours, then the precipitated crystals are collected by filtration and triturated with saturated sodium bicarbonate until pH 7-8 is achieved. The crystals are washed with water and dried in vacuo to give 63.0 g of the product as cream colored crystals, mp 122-125° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:27])([C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1)[CH3:27]
Reactant: Cc1cnc(C(C)(C)N)s1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: Cc1cnc(C(C)(C)NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)s1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α,α,5-trimethyl-2-thiazolemethanamine (CAN 1155530-59-8) as starting materials; LC-MS (UV peak area/ESI) 94%, 372.1743 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)[C:9]1=[O:37])(=O)=O.[NH4+:38].[OH-]>CC(O)C.O>[NH2:38][CH2:6][CH2:7][N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)[N:10]([C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[CH:27][CH:28]=2)[C:9]1=[O:37]
Reactant: [NH4+]
Reactant: CS(=O)(=O)OCCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: NCCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 80 °C
Yield: 96 %

Procedure:
2-(3-(4-(4-Chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)ethyl methanesulfonate (85.0 mg, 0.153 mmol) is dissolved in a mixture solvent of iPrOH (0.5 mL) and concentrated ammonia aqueous solution (0.5 mL). The reaction mixture is heated at 80° C. for 2 h, cooled down to room temperature, taken in H2O (10 mL), and extracted with EtOAc (3×5 mL). The combined organic layer is dried over MgSO4 and evaporated in vacuo to provide the crude title compound (69.7 mg, 96% yield) as a colorless oil-like product; HPLC-MS calculated for C24H21ClF3N3O2 (M+H+) 476.1, found 476.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([N:31]=[C:32]=[O:33])(=[O:30])=[O:29])=[O:21].O1CCOCC1>C(#N)C>[CH3:18][O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH:31][C:32]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)=[O:33])(=[O:29])=[O:30])=[O:21]
Reactant: COc1cc(CSc2ccccn2)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: C1COCCO1
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(CSc2ccccn2)cc(OC)n1

Procedure:
7.0 g of 2-amino-4-methoxy-6-(pyridin-2-ylthiomethyl)-pyrimidine and 6.8 g of 2-methoxycarbonylphenylsulfonylisocyanate are stirred in 50 ml of abs. acetonitrile for 2 hours at 20°-25° C. The turbid solution is filtered, and the solvent evaporated off in vacuo. The residue is crystallised from dioxane to thus obtain 5.5 g (37% of theory) of N-(2-methoxycarbonylphenyl-sulfonyl)-N'-[4-methoxy-6-(pyridin-2-ylthiomethyl)-pyrimidin-2-yl]-urea, which crystallises with 0.5 mol of dioxane, m.p. 175°-181° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[CH:7][N:6]=1.O1CCCC1.Cl[CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28]>CCOCC>[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28][N:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[N:6][CH:7]=1)[C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13]
Reactant: COc1ccc(NC(=O)C2CC2)cn1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCCOCN(C(=O)C1CC1)c1ccc(OC)nc1
Reaction time: 8 h
Yield: 61.2 %

Procedure:
Sodium hydride (0.33 g, 0.014 mol) and N-(2-methoxy-5-pyridyl)-cyclopropane carboxamide (92.5 g, 0.014 mol) were added to dry tetrahydrofuran (THF). This mixture was stirred under N2 for one hour when methoxyethyl chloromethyl ether (1.6 g, 0.014 mol) was added dropwise to the stirred mixture. The reaction was stirred overnight and diluted with ether and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo nto give 2.4 g of a yellow oil of the title compound. The structure was confirmed by mass spectroscopy (MS), IR and NMR analysis.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:5]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[CH:2]([CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:6][CH:5]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)COc1ccc(CCO)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)COc1ccc(CC=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of 18 (20.0 g, 0.083 mole) in anhydrous dichloromethane (200 ml) was added pyridinium chlorochromate (PCC) (44.7 g, 0.207 mole) and the mixture was stirred at room temperature for two hours. Ether (500 ml) was then added to quench the reaction and the mixture was then filtered through C elite. (Trade Mark) Evaporation of the solvents in vacuo afforded the crude product which was purified by flash chromatography on silica gel using 20% ethyl acetate in hexane to give 19 (16.6 g, 80%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:40])([F:39])[F:30])=[CH:33][CH:34]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(C(F)(F)F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethyl)phenol: ESMS m/e: 543.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[N:28]1.N1CCCCC1>CO>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:8]2\[O:9][C:5]3[C:4]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]4)=[C:3]([OH:26])[C:2]([Cl:1])=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:28]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
A solution of tert-butyl 4-[(5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.261 mmol) in methanol (1 mL) was added with indazole-3-carbaldehyde (0.0381 g, 0.261 mmol), and piperidine (0.00222 g, 0.0261 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, then added with methanol (4 mL), suspended in methanol and thereby washed, and the solid was collected by filtration to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0890 g, 66%).