Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]2=[O:22])=[C:4]([CH3:23])[CH:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]([C:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]=2[O:22][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(C)c1C1C(=O)CC(CC2CCOCC2)C1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Br)cc(C)c1C1=C(OC(=O)C(C)(C)C)CC(CC2CCOCC2)C1=O

Procedure:
To a solution of rac-2-(4-bromo-2,6-dimethylphenyl)-4-(tetrahydropyran-4-ylmethyl)cyclopentane-1,3-dione (1.0 g, 2.6 mmol) in dichloromethane (20 ml) is added triethylamine (1.09 ml, 7.8 mmol) then pivaloyl chloride (1.10 ml, 7.8 mmol), and the resulting solution is stirred at room temperature for 4 hours. The reaction mixture is diluted with dichloromethane (100 ml), washed with distilled water (50 ml×3), and the organic fractions are combined, dried over sodium sulphate, filtered and the filtrate concentrated in vacuo to afford rac-2,2-dimethylpropionic acid 2-(4-bromo-2,6-dimethylphenyl)-3-oxo-4-(tetrahydropyran-4-ylmethyl)cyclopent-1-enyl ester. This material is used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([O:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:22]=2)[NH:19][C:18]([C:30](=[S:32])[NH2:31])=[CH:17]3)=[CH:9][CH:8]=1.[C:33]([O:38][CH2:39][CH3:40])(=[O:37])[C:34]#[C:35][CH3:36].C(P(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1.C1(C)C=CC=CC=1.CCCCCC>[CH2:39]([O:38][C:33](=[O:37])[CH2:34][CH:35]1[S:32][C:30]([C:18]2[NH:19][C:20]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:13][C:10]2[CH:11]=[N:12][C:7]([CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:8][CH:9]=2)=[CH:22][C:21]=3[O:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[N:31][CH2:36]1)[CH3:40]
Reactant: COCCOCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=S)cc3c2)cn1
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COCCOC)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Temperature: 90 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a solution of 5-({6-[(2-methoxyethoxy)methyl]pyridin-3-yl}oxy)-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carbothioamide (1.1 g) in tetrahydrofuran (10 mL) and toluene (15 mL) were added ethyl 2-butynoate (0.67 g) and tri-n-butylphosphine (0.49 g), and the mixture was stirred at 90° C. for 1 hr. The reaction mixture was cooled, and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 50:50, volume ratio) to give the title compound (445 mg, yield 32%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1.O1CCCC1>[CH3:11][C:3]1[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[NH:1][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(N)c(C)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(C)c1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
4'-Amino-3'-methylacetophenone from Step VIII (3.0 g, 20 mmol) in 15 ml of dry pyridine at 5° C. is reacted with 3.0 g (26.2 mmol) of methanesulfonyl chloride in 5 ml of tetrahydrofuran. The reaction is stirred at 5° C. for 2 hrs, then at room temperature overnight. The reaction is diluted with ice-water. The solid is collected, washed with water, air dried and crystallized from methylene chloride-pet. ether to yield the title compound; m.p. 152°-153° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)([C:10]2[N:11](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=[CH:13][N:14]=2)[OH:9])=[CH:4][CH:3]=1.Cl.N>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)([C:10]2[NH:14][CH:13]=[CH:12][N:11]=2)[OH:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccnc2C(O)(c2ccc(F)cc2)c2ccc(F)cc2)cc1
Agent: Cl
Agent: N
Solvent: O
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)c1ncc[nH]1

Procedure:
A mixture of 10 g. (0.0227 mol) of α,α-bis(p-fluorophenyl)-1-(toluene-p-sulphonyl)imidazole-2-methanol, 34 ml. of 2 N hydrochloric acid solution (0.0681 mol) and 225 ml. of water was boiled under reflux for 5 hours. After cooling, the mixture was made alkaline by addition of ammonia. The base obtained was crystallised from isopropyl alcohol; its melting point was 198°-200° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH:19]([CH:25](OC)OC)[CH:20](OC)OC)[CH2:15][C@H:14]1[C@@H:13]([CH3:30])[S:12][C:11]([NH:31]C(=O)C1C=CC=CC=1)=[N:10]2.[CH3:40][NH:41][NH2:42].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]12[CH2:18][O:17][CH:16]([C:19]3[CH:25]=[N:42][N:41]([CH3:40])[CH:20]=3)[CH2:15][CH:14]1[CH:13]([CH3:30])[S:12][C:11]([NH2:31])=[N:10]2
Reactant: COC(OC)C(C(OC)OC)[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Reactant: CNN
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1SC(N)=NC2(c3ccc(F)cc3F)COC(c3cnn(C)c3)CC12
Temperature: 70 °C

Procedure:
N-[(4R,4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-4-methyl-6-(1,1,3,3-tetramethoxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C75) [prepared from P4 via a method similar to that used for the conversion of P1 to C44 in Preparation P3 and Example 5] (297 mg, 0.526 mmol) was combined with ethanol (1.75 mL) and methyl hydrazine (36.4 mg, 0.789 mmol) followed by addition of water (0.6 mL). Concentrated sulfuric acid (55 μL, 1.0 mmol) was slowly added and the reaction mixture was heated at 70° C. for 18 hours. Saturated aqueous sodium bicarbonate solution was added, and the aqueous layer was extracted three times with ethyl acetate; the combined organic layers were extracted three times with 0.2 M aqueous hydrochloric acid, and the combined aqueous layers were washed with ethyl acetate. The pH was adjusted to 9-10 by addition of 1 M aqueous sodium hydroxide solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0% to 15% methanol in dichloromethane) provided the product as an off-white solid. Yield: 109 mg, 0.287 mmol, 55%. LCMS m/z 379.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.48 (s, 1H), 7.36 (s, 1H), 7.22-7.28 (m, 1H), 6.85-6.92 (m, 2H), 4.57 (dd, J=11.3, 2.3 Hz, 1H), 4.16 (dd, J=11.1, 2.1 Hz, 1H), 3.76 (s, 3H), 3.69 (d, J=11.3, 1H), 3.01-3.06 (m, 1H), 2.78 (dt, J=11.9, 3.8 Hz, 1H), 1.75-1.80 (m, 1H), 1.59-1.68 (m, 1H), 1.10 (d, J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:12]=1[C:13]#[N:14].[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:10][C:11]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:12]=2[C:13]#[N:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1cc(I)c(Cl)cn1
Reactant: N#Cc1cc(F)ccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1cc(F)ccc1Nc1cc(Cl)ncc1Cl
Yield: 86 %

Procedure:
To a degassed solution of 2,5-dichloro-4-iodopyridine (8 g, 29.2 mmol), 2-amino-5-fluorobenzonitrile (3.98 g, 29.2 mmol) and potassium triphosphate (18.60 g, 88 mmol) in 1,4-dioxane (100 ml) stirred under nitrogen at the room temperature was added DPEPhos (1.258 g, 2.337 mmol) and palladium acetate (0.262 g, 1.168 mmol). The reaction mixture was stirred at the reflux for 18 hr. The reaction mixture was filtered. The solvent was evaporated. Ether (50 ml) was added and the solid was filtered. 2-[(2,5-Dichloro-4-pyridinyl)amino]-5-fluorobenzonitrile (7.09 g, 25.1 mmol, 86% yield) was isolated as an orange solid. 1H NMR (400 MHz, METHANOL-d4) ppm 6.44 (s, 1 H) 7.46-7.58 (m, 2 H) 7.66 (dd, J=8.08, 2.78 Hz, 1 H) 8.08 (s, 1 H); HPLC Rt=3.23 min, MS (ESI): 382.0, 384.19 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:7][C:6]1[C:2]([Cl:1])=[C:3]([C:8]([O:10][CH3:11])=[O:9])[S:4][CH:5]=1
Reactant: COC(=O)c1scc(C)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1scc(CBr)c1Cl
Yield: 38.5 %

Procedure:
A solution of methyl 3-chloro-4-methylthiophenecarboxylate (10 g, 53 mmol), N-bromosuccinimide (9.4 g, 53 mmol) and azo-bis-(isobutyronitrile) (860 mg, 5.3 mmol) in carbon tetrachloride (300 ml) was heated at reflux for 18 h. The mixture was filtered and reduced. Chromatography (10% EtOAc/90% hexanes) afforded methyl 4-bromomethyl-3-chlorothiophene-2-carboxylate (5.5 g, 39%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:6][C:5]2=[O:20].[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]=O)=[CH:27][CH:28]=1.Cl>C(O)C>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]=[C:6]2[C:5](=[O:20])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[O:8][CH:7]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:27][CH:28]=1
Reactant: COc1ccc(C2CC(=O)c3cc(O)ccc3O2)cc1
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(C=C2C(=O)c3cc(O)ccc3OC2c2ccc(OC)cc2)cc1
Reaction time: 3 h

Procedure:
A hot solution of 27 g of 6-hydroxy-4'-methoxyflavanone and 13.6 g of anisaldehyde in 1,400 ml of ethanol is saturated with HCl and is left for 3 hours to cool; precipitation with water gives 3-p-methoxybenzylidene-6-hydroxy-4'-methoxyflavanone, m.p. 199°-201°.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([C:21]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:22])[C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:10]=2[CH:20]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([C:21]([O:23][CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:22])[C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:11][C:10]=2[CH:20]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Nc1cc(C(=O)OCCN2CCCCC2)c2oc(-c3ccccc3)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(C(=O)OCCN2CCCCC2)c2oc(-c3ccccc3)cc2c1
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
A solution of 147 mg of acetyl chloride in 2 ml of toluene is added dropwise to a mixture of 522 mg of 2-piperidinoethyl 5-amino-2-phenylbenzofuran-7-carboxylate, 210 mg of sodium bicarbonate and 10 ml of ethyl acetate under ice-cooling. The mixture is stirred at the same temperature for 30 minutes and the reaction mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is recrystallized from ethyl acetate to give 467 mg of 2-piperidinoethyl 5-acetamido-2-phenylbenzofuran-7-carboxylate as pale yellow needles.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([C:12]([O:14]C)=[O:13])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].Cl>C1COCC1.O>[CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: COC(=O)c1cccc2c1NC(C)(C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCc2cccc(C(=O)O)c2N1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2,2-dimethyl-1,2,3,4-tetrahydroquinoline-8-carboxylate (0.138 g, 0.629 mmol) in THF (5 mL) and H2O (5 mL) was added a 1N aqueous solution of sodium hydroxide (1.88 mL, 1.88 mmol). After stirring at 50° C. overnight the reaction mixture was acidified to pH 2 using 1N aqueous HCl, extracted with ethyl acetate (three times), dried over MgSO4 and concentrated under vacuum to afford the desired compound that was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:12]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:23])[NH:17]2)[O:4][Si](C(C)(C)C)(C)C.N(C[C@@H](C1C=CC(OCC2C=CC=CC=2)=C2C=1C=CC(=O)N2)O)=[N+]=[N-]>>[NH2:1][CH2:2][C@@H:3]([C:12]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:23])[NH:17]2)[OH:4]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Product: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 2, using Intermediate 5 as a substrate. ES/MS calcd. for C11H13N2O3+ 221.1. Found m/z=221.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:29]3[CH2:34][CH2:33][C@H:32]([C:35]([O:37]CC)=[O:36])[CH2:31][CH2:30]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[O:19][C:20]5[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:21]=5[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12.[OH-].[Na+].Cl>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:29]3[CH2:34][CH2:33][C@H:32]([C:35]([OH:37])=[O:36])[CH2:31][CH2:30]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[O:19][C:20]5[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:21]=5[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: CCOC(=O)[C@H]1CC[C@@H](n2nc(-c3ccc(Nc4nc5cc(C)cc(C)c5o4)cc3)c3c(N)ncnc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](C(=O)O)CC5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 70 °C

Procedure:
cis-Ethyl 4-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-cyclohexanecarboxylate (0.10 g, 0.19 mmol), aqueous sodium hydroxide (1 M, 2 mL, 2 mmol), and methanol (2 mL) were combined and heated under an air condenser at 70° C. for 14 h. The residue was acidified with aqueous hydrochloric acid (3 M, 2 mL, 6 mmol), and extracted with 10% methanol/dichloromethane (3×20 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 8.8-10.9 min) afforded cis-4-(4-Amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-cyclohexanecarboxylic acid as a cream-colored powder (0.026 g, 0.052 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 9.03 min; MS (MH)+ 498.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]1=[O:33].O1CCOCC1.CN[C@H]1CCCC[C@@H]1NC.C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[O:33]=[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][N:27]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Br)cc4)CC3)C2)c2ccccc21
Reactant: O=c1cccc[nH]1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-n5ccccc5=O)cc4)CC3)C2)c2ccccc21
Temperature: 160 °C

Procedure:
To a solution of (1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (30.0 mg, 0.0000728 mol, example 238), pyrid-2-one (8.30 mg, 0.0000873 mol) in 1,4-dioxane (2 mL, 0.02 mol) were added (1S,2S)-N,N′-dimethylcyclohexane-1,2-diamine (2.1 mg, 0.000014 mol), copper(I) iodide (1.4 mg, 0.0000073 mol), and potassium carbonate (21.1 mg, 0.000153 mol). The mixture was heated at 160° C. for 60 minutes. The reaction mixture was filtered, and the filtrate was concentrated and purified using prep-HPLC. LC/MS: 427.1 (M+H+).
Reaction SMILES: [OH-:1].[K+].O.[OH:4][C:5]1([C:18](N)=[O:19])[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[O:8][CH2:7][CH2:6]1>CC(O)C>[Cl:17][C:10]1[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[C:14]2[C:9]=1[O:8][CH2:7][CH2:6][C:5]2([C:18]([OH:19])=[O:1])[OH:4]
Reactant: COc1cc(Cl)c2c(c1)C(O)(C(N)=O)CCO2
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: COc1cc(Cl)c2c(c1)C(O)(C(=O)O)CCO2

Procedure:
KOH (1.2 g; 21 mmol) and water (25 mL) were added to a solution of 4-hydroxy-8-chloro-6-methoxychroman-4-yl-carboxylic amide (0.39 g; 1.5 mmol; from step (iv) above) in i-PrOH (25 mL). The reaction mixture was refluxed overnight, i-PrOH was evaporated and the water solution was washed with ether. The reaction mixture was acidified with HCl (2M) and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and evaporated. Yield: 0.38 mg (97%).
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:17]=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[NH2:1][C:2]1([C:9]2[CH:17]=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)[CH2:7][CH2:6][CH:5]([N:18]2[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:24])[CH2:19]2)[CH2:4][CH2:3]1
Reactant: NC1(c2ccc3c(c2)OCO3)CCC(=O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: NC1(c2ccc3c(c2)OCO3)CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-amino-4-benzo[1,3]dioxol-5-yl-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:11]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CCc1ccccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccccc1OCc1ccccc1
Temperature: 90 °C
Yield: 120.2 %

Procedure:
(2-Hydro xyphenyl)acetonitrile (1.01 g, 0.0076 mol) was dissolved in DMF (10 ml), and to this solution were successively added benzyl bromide (0.90 ml, 0.0076 mol, 1.0 eq) and anhydrous potassium carbonate (2.1 g, 0.015 mol, 3.0 eq). The mixture was stirred with heating at 90° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and water (10 ml) was added. The mixture was extracted twice with ethyl acetate (30 ml). The organic layers were combined, washed with saturated brine (60 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give (2-benzyloxyphenyl)acetonitrile (2.04 g, 100%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=O)[CH2:6][C:7](=[O:18])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[F:17])[CH3:2].C([O-])(=O)C.[NH4+:25]>CCO>[CH2:1]([O:3][C:4](=[O:20])/[C:5](/[NH2:25])=[CH:6]/[C:7](=[O:18])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[F:17])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)cc1F
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)/C(N)=C/C(=O)/C=C/c1ccc(Cl)cc1F
Yield: 59.1 %

Procedure:
A mixture of (E)-6-(4-chloro-2-fluorophenyl)-2,4-dioxo-hex-5-enoic acid ethyl ester (3; 15.0 g, 0.05 mol) and ammonium acetate (7.7 g, 0.1 mol) in EtOH (100 mL) was stirred and heated to reflux for 1 h. The solvent was removed under reduced pressure, and the residue was dissolved in CH2Cl2 (200 mL) and washed with saturated aqueous sodium carbonate (Na2CO3, 100 mL). After drying over MgSO4, silica gel (50 g) was added and the solvent was removed. The residue was washed with 20% ethyl acetate (EtOAc)/hexanes (300 mL) to give after solvent removal (2Z,5E)-2-amino-6-(4-chloro-2-fluorophenyl)-4-oxo-hexa-2,5-dienoic acid ethyl ester (7; 6.1 g, 41%) as a light orange solid: mp 102-103° C.; 1H NMR (400 MHz, CDCl3) δ 9.4 (br s, 1H), 7.62 (d, J=15.9 Hz, 1H), 7.52 (t, J=8.5 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.19-7.08 (m, 2H), 6.87 (d, J=15.9 Hz, 1H), 6.14 (s, 1H), 6.05 (br s, 1H), 4.37 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H); HRMS-ESI (m/z): calcd for C14H13ClFNO3, 297.056. found, 297.056. Further washing of the silica gel with 40% EtOAc/hexanes (400 mL) gave more (2Z,5E)-2-amino-6-(4-chloro-2-fluorophenyl)-4-oxo-hexa-2,5-dienoic acid ethyl ester (7; 8.8 g of 70% pure by 1H NMR spectroscopy) for a total of 12.2 g (82%).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[CH3:12][O:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:33])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]4[O:11][CH2:1][O:2][C:3]=4[CH:4]=3)[C:24]3[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)c(C)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc4c(c3)OCO4)c3c(C)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxy-benzylamine is reacted with 4-(4-chloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxybenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=3)[NH:30][N:29]=2)=[CH:23][CH:22]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:37][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:35]=3)[NH:30][N:29]=2)=[CH:25][CH:26]=1
Reactant: Nc1ccc2[nH]nc(Nc3ccc(F)cc3)c2c1
Reactant: CC1=C(C(=O)O)C(c2cc(F)cc(F)c2)NC(=O)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4ccc(F)cc4)c3c2)C(c2cc(F)cc(F)c2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(3,5-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(4-fluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=493 [M+H]+.