Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:30]4[C:25](=[CH:26][C:27](Br)=[CH:28][CH:29]=4)[O:24][CH2:23][C:22]=3[CH:32]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH2:42][CH:41]1[C:45]1[NH:49][C:48]2[CH:50]=[C:51](B3OC(C)(C)C(C)(C)O3)[CH:52]=[CH:53][C:47]=2[N:46]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([C:51]5[CH:52]=[CH:53][C:47]6[N:46]=[C:45]([CH:41]7[CH2:42][CH2:43][CH2:44][N:40]7[C:38]([O:37][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:39])[NH:49][C:48]=6[CH:50]=5)=[CH:28][CH:29]=4)[O:24][CH2:23][C:22]=3[CH:32]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)COc2cc(Br)ccc2-3)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)COc2cc(-c4ccc5nc(C6CCCN6C(=O)OC(C)(C)C)[nH]c5c4)ccc2-3)[nH]1
Temperature: 90 °C
Yield: 29.9 %

Procedure:
To the solution of 2-[5-(3-Bromo-6H-benzo[c]chromen-8-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (9 mg, 0.02 mmol) and 2-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (9.6 mg, 0.02 mmol) in DME (0.75 ml) and water (0.25 ml) was added potassium carbonate (10 mg, 0.07 mmol), followed by Pd(PPh3)4 (2 mg) and PdCl2(dppf)CH2Cl2 (2 mg). The mixture was heated at 90° C. for 6 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (EtOAc) gave 2-(5-{3-[2-(1-t-butoxycarbonyl-pyrrolidin-2-yl)-3H-benzoimidazol-5-yl]-6H-benzo[c]chromen-8-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (4.2 mg). m/z: 729.2 (M+1), 727.3 (M−1), 365.2 (M+2)/2.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)([OH:11])[C:7]([F:10])([F:9])[F:8].[H-].[Na+].[CH3:19]I>C(COC)OC>[CH3:19][O:11][C:6]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[C:7]([F:9])([F:10])[F:8]
Reactant: OC(c1nccs1)(c1nccs1)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(c1nccs1)(c1nccs1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
1, 1-Di(2-thiazolyl) -2,2,2-trifluoroethanol (1 g) was added to a stirred suspension of sodium hydride (80%, 225 mg) in dry dimethoxyethane (50 ml) at 0° C. After 15 minutes, methyl iodide (2.1 g) was added dropwise. The mixture was allowed to warm to room temperature and was then left stirring overnight. The mixture was concentrated by evaporation, then poured into saturated aqueous sodium chloride solution and extracted with dichloromethane. The material thus obtained was purified by flash chromatography to give the title compound as a white solid (950 mg). M.p. 40°-41° C. 13C Nmr (CDCl3) 54.9, 82.9 (g, J 30 Hz), 122.2, 122.8 (q, J 287 Hz), 143.2 and 163.6 ppm. Found: C, 38.7; H, 2.4; N, 9.9. C9H7F3N2OS2 requires C, 38.6; H, 2.5; N, 10.0%
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([C:12](O)=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O.O.C[N:33]([CH:35]=[O:36])C>>[C:24]1([C:22]2[N:33]=[C:35]([CH2:12][C:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=4[O:10][CH:9]=3)[O:36][CH:21]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN(C)C=O
Reactant: O=C(CBr)c1ccccc1
Reactant: COc1cccc2c(C(=O)O)coc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cccc2c(Cc3nc(-c4ccccc4)co3)coc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
7-methoxy-benzofuran-3-carboxylic acid (294 mg) was dissolved in DMF (5 ml). To this solution, potassium carbonate (237 mg) and phenacyl bromide (342 mg) were added, and the resulting solution was stirred at room temperature for 30 minutes. The reaction mixture was poured into water layer (50 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. Sodium sulfate was removed by filtration and the solvent was removed under reduced pressure. The residue was dissolved in acetic acid (5 ml) and ammonium acetate (551 mg) was added, followed by refluxing the resulting solution for 4 hours. After cooling the reaction solution to room temperature, the solution was poured into water layer (100 ml) and extracted twice with ethyl acetate (30 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1) using silica gel to obtain the desired compound (203 mg, yield: 47%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:25](=[O:31])[C:26]([O:28]CC)=[O:27])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:25](=[O:31])[C:26]([OH:28])=[O:27])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(F)c(Cl)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(F)c(Cl)c3)cc12
Yield: 63.1 %

Procedure:
[1-Benzyl-5-(3-chloro-4-fluorophenyl)-1H-indol-3-yl](oxo)acetic acid was prepared from ethyl [1-benzyl-5-(3-chloro-4-fluorophenyl)-1H-indol-3-yl](oxo)acetate (0.540 g, 1.24 mmol), and potassium hydroxide (0.218 g, 3.89 mmol) in THF (6 mL) and water (6 mL) according to the procedure described in Step 4 of Example 5. Purification by crystallization from methylene chloride/hexane and drying at 85° C. furnished the title compound as a white solid (0.319 g, 63%), mp: 145-146° C. (dec.). Mass spectrum (+APCI, [M+H]+) m/z 408; 1HNMR (400 MHz, DMSO-d6): δ 13.8-14.3 (br s, 1H), 8.75 (s, 1H), 8.4 (d, 1H, J=1.7 Hz), 7.8 (dd, 1H, J=7.2 Hz and 2.3 Hz), 7.65-7.7 (m, 2H), 7.6 (dd, 1H, J=8.5 Hz and 2.0 Hz), 7.5 (t, 1H, J=8.9 Hz), 7.25-7.35 (m, 5H), and 5.6 ppm (s, 2H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[C:8]([NH2:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.Cl>ClCCl.CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[C:8]([NH2:10])=[O:9])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: NC(=O)[C@H]1CCCC[C@H]1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)[C@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Yield: 53.2 %

Procedure:
A mixture of (1S,2R)-2-aminocyclohexanecarboxylic acid amide (16.2 mmol), 4-chlorobenzenesulfonylchloride (6.84 g, 32.4 mmol), and triethylamine (20 mL, 143 mmol) were stirred in dichloromethane/DMF (500 mL/100 mL) at room temperature for 6 h. The crude mixture was poured into 1 M hydrochloric acid (500 mL). The organic layer was collected and washed with with water (2×500 mL). Hexanes (50 mL) were added to the organic layer. The combined mixture was sequentially washed with water (500 mL) and brine (50 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (solvent gradient: methanol/chloroform, 0.25% to 5.0%) to afford 2.73 g (53% yield, 5 steps) of (1S,2R)-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide. An analytical sample was obtained after recrystallization from ethyl acetate/hexanes: 1H NMR (400 MHz, DMSO-d6) 7.82 (d, 2 H, J=8.5), 7.64 (d, 2 H, J=8.6), 7.57 (d, 1 H, J=7.1), 7.22 (s, 1 H), 6.79 (s, 1 H), 3.43 (m, 1 H), 2.36 (m, 1 H), 1.72 (m, 2 H), 1.46 (m, 3 H), 1.17 (m, 3 H); MS m/e 339.1 (M+Na)+. Anal. calcd. for C13 H17ClN2O3S: C, 49.28; H, 5.40; N, 8.84. Found: C, 49.55; H, 5.24; N, 8.78. Optical rotation: [α]D=−55.8 (c=6.78 mg/mL, DMF).
Reaction SMILES: [CH2:1]([C@H:8]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:9]([OH:32])[CH2:10][N:11](CC1C=CC=CC=1)[NH:12][C:13](=[O:24])[C@@H:14]([NH:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH2:1]([C@H:8]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:9]([OH:32])[CH2:10][NH:11][NH:12][C:13](=[O:24])[C@@H:14]([NH:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COC(=O)N[C@H](C(=O)NNC[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Yield: 96.4 %

Procedure:
A solution of Example 5F (0.115 g, 0.2 mmol) in methanol (2 mL) was treated with Pd(OH)2 (38 mg) and 4N HCl (52 μL, 1 equivalent) and a hydrogen balloon at 25° C. for 3.5 hrs. The solvents were evaporated, and the crude residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and the solvents were evaporated to give 90 mg (93%) of the title compound.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.Cl.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30].C(N(CC)CC)C>ClCCl>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1
Reactant: NCC(F)(F)F
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1ccccc1-c1nc2nc(NCC(F)(F)F)ncc2c(=O)[nH]1
Reaction time: 96 h

Procedure:
A solution of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.72 g), 2,2,2-trifluoroethylamine hydrochloride (0.97 g) and triethylamine (0.73 g) in dichloromethane (15 ml) was stirred at ambient temperature for 48 hours and allowed to stand for 4 days. A yellow solid had formed which was collected by filtration and washed with dichloromethane. The filtrate was washed with dilute hydrochloric acid (15 ml) then water (10 ml) and the aqueous layers extracted with dichloromethane (2×7.5 ml). The combined organic layers were dried (magnesium sulphate) and evaporated under reduced pressure to yield a crude product. This was eluted from a silica column with diethyl ether:chloroform (4:1) and the combined fractions containing product were evaporated under reduced pressure to yield a residue which was recrystallized from isopropanol to yield the title compound, 0.13 g, m.p. 214-215.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1.[CH3:13][O-:14].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([O:14][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1
Reactant: C[O-]
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)nc(C)c1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 65.2 %

Procedure:
2,4-Dichloro-6-methyl-5-nitropyrimidine (3.0 g, 14.4 mmol) was dissolved in methanol (30 mL). The solution was cooled to −10° C. and sodium methoxide (25% in methanol, 3.3 mL, 14.4 mmol) was added drop wise. After 10 minutes, the solution was quenched with acetic acid (5 mL) and concentrated. The residue was suspended in saturated sodium bicarbonate and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Flash chromatography (5% ethyl acetate/hexanes) gave 1.91 g (65% yield) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:63]1([CH2:68][CH:69]2[CH2:74][CH2:73][CH2:72][NH:71][CH2:70]2)[CH2:67][CH2:66][CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:71]1[CH2:72][CH2:73][CH2:74][CH:69]([CH2:68][N:63]3[CH2:64][CH2:65][CH2:66][CH2:67]3)[CH2:70]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: C1CNCC(CN2CCCC2)C1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCC(CN4CCCC4)C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 3-(pyrrolidin-1-ylmethyl)-piperidine in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][C:2](=[CH2:27])[CH:3]([N:8]1[C:11](=[O:12])[CH:10]([N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH:9]1[S:24]([OH:26])=O)[C:4]([O:6][CH3:7])=[O:5].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.ClCCCl.C(OCC)(=O)C>[Cl-].[Na+].O>[C:17]1(=[O:18])[N:13]([CH:10]2[C:11](=[O:12])[N:8]3[CH:3]([C:4]([O:6][CH3:7])=[O:5])[C:2](=[CH2:1])[CH2:27][S:24](=[O:26])[C@H:9]23)[C:14](=[O:23])[C:15]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]12
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1S(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CCOC(C)=O
Product: C=C1CS(=O)[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)OC
Temperature: 25 °C

Procedure:
A solution of 0.10 g. of methyl 3-methyl-2-(2-sulfino-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate and 0.04 g. of phosphorous pentoxide in 20 ml. of 1,2-dichloroethane was stirred at room temperature for 1 hour. A tlc of the reaction mixture indicated only trace amounts of the methylenecepham sulfoxide. The mixture was then refluxed for 30 minutes, cooled to room temperature, and combined with 25 ml. of ethyl acetate and 50 ml. of brine. The organic layer was separated, washed with aqueous sodium bicarbonate and brine and dried (MgSO4). Evaporation in vacuo to dryness provided 0.04 g. of the title product as a white froth.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH:5]1[CH:10]=[C:9]2[CH:11](O)[C:12]3[C:17]([O:18][C:8]2=[CH:7][CH:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[CH2:20]([N:22](CC)CC)C.C(=O)=O>C1C=CC=CC=1>[CH3:1][N:2]([CH:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[O:18][C:8]2[C:9]1=[CH:10][CH:5]=[CH:6][CH:7]=2)[C:3]([NH:22][CH3:20])=[O:4]
Reactant: CCN(CC)CC
Reactant: CN=C=O
Reactant: OC1c2ccccc2Oc2ccccc21
Agent: O=C=O
Solvent: c1ccccc1
Product: CNC(=O)N(C)C1c2ccccc2Oc2ccccc21

Procedure:
Methyl isocyanate (25 ml.) was slowly added to a solution of xanthydrol (30 g.) and triethylamine (1 ml.) in benzene (120 ml.) at 65°C. The solution was kept at 55°C. until evolution of carbon dioxide ceased, refluxed for 11/2 hours, cooled and filtered. The solid was collected and recrystallised from benzene to give N,N'-dimethyl-N-9-xanthenylurea solvated with 2 molecules of benzene, m.p. 170°-171°C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:8][CH2:9][C:10]1[NH:11][C:12](=[O:20])[C:13]2[CH2:19][O:18][CH2:17][CH2:16][C:14]=2[N:15]=1)[CH3:7].[F:21][C:22]1[CH:39]=[CH:38][C:25]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:35](O)=[O:36])[CH2:30][CH2:29]2)=[O:27])=[CH:24][CH:23]=1.CC#N.O>C(O)=O>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([CH:28]2[CH2:29][CH2:30][N:31]([CH2:34][C:35]([N:8]([CH2:9][C:10]3[NH:11][C:12](=[O:20])[C:13]4[CH2:19][O:18][CH2:17][CH2:16][C:14]=4[N:15]=3)[CH:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH3:7])=[O:36])[CH2:32][CH2:33]2)=[O:27])=[CH:38][CH:39]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CC(NCc1nc2c(c(=O)[nH]1)COCC2)c1cccs1
Solvent: O=CO
Solvent: CC#N
Solvent: O
Product: CC(c1cccs1)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following the general procedure of Example 1, the title compound was prepared (0.02 g) from 2-((1-(thiophen-2-yl)ethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. 1H NMR (400 MHz, MeOD) δ ppm 8.04-8.17 (m, 2H), 7.22-7.46 (m, 3H), 6.99-7.17 (m, 1H), 6.86-6.95 (m, 1H), 6.09-6.24 (m, 1H), 5.36-5.47 (m, 1H), 4.24-4.64 (m, 6H), 3.85-3.95 (m, 2H), 3.69-3.83 (m, 2H), 3.38-3.64 (m, 1H), 3.11-3.27 (m, 1H), 2.49-2.68 (m, 2H), 1.99-2.26 (m, 4H), 1.74-1.85 (m, 1H), 1.55 (d, J=7.03 Hz, 2H). HRMS calculated for C29H31F1N4O4S1 539.2128. found (ESI, [M+H]+) 539.2128. MS (ESI) m/z 539.2. (M+H)+. Retention time: 3.21 min (5-95% CH3CN/H2O over 7.75 min with 0.1% formic acid, Inertsil ODS3 100×3 mm C18 column with flow rate of 1.0 mL/min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:37]1[CH2:41][CH2:40][N:39]=[C:38]1[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][NH:49][CH3:50])=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>ClCCCl.CN(C=O)C>[NH:39]1[CH2:40][CH2:41][N:37]=[C:38]1[C:42]1[CH:43]=[CH:44][C:45]([CH2:48][N:49]([CH3:50])[C:21]([C:18]2[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]3[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=3[CH3:9])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=2)=[O:22])=[CH:46][CH:47]=1
Reactant: CNCc1ccc(C2=NCCN2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(C4=NCCN4)cc3)co2)c(C)c1
Temperature: 25 °C

Procedure:
5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (30 mg, 0.09 mmol) was dissolved in DCE (2 mL) and CDI (30 mg, 0.18 mmol) added. The reaction was stirred at room temperature until complete as determined by LCMS. 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylmethanamine (32 mg, 0.17 mmol) and DIPEA (0.032 mL, 0.18 mmol) was added and the reaction stirred for 3 days at ambient temperature. A further 32 mg 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylmethanamine was added, followed by DMF (0.5 mL) and the reaction was stirred for 18 h. The reaction was washed with saturated aqueous NH4Cl (3×5 mL) and the organic layer dried over MgSO4, shaken with PL-MIA and Ambersep resins, and concentrated. A portion of the crude product was purified using prep method C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8](C(O)=O)([C:17]([OH:19])=[O:18])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].C(O)=O>C(OCC)(=O)C>[C:13]([O:12][C:10](=[O:11])[CH2:9][CH:8]([C:17]([OH:19])=[O:18])[CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:23])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)CC(CC(=O)OC(C)(C)C)(C(=O)O)C(=O)O
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(CC(=O)OC(C)(C)C)C(=O)O
Temperature: 80 °C

Procedure:
The compound of Example 166 (170 mg, 0.512 mmol) was dissolved in ethyl acetate. Formic acid (61 μL, 1.53 mmol) was added and the mixture was heated at 80° C. for 3 h. After cooling to room temperature, the reaction mixture was extracted three times with water, dried (sodium sulfate), filtered and evaporated to dryness. 1H NMR(CDCl3, 300 MHz): 1.43(s, 18H); 2.50, 2.65(2dd, J1=16.7 Hz, J2=6.2 Hz, 4H); 3.20(p, J=6.2 Hz, 1H).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[F:16])[NH:12][CH:11]=[CH:10]2.[C:17](=[O:19])=[O:18].O>CCCCCC.C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([C:17]([OH:19])=[O:18])[C:15]=1[F:16])[NH:12][CH:11]=[CH:10]2
Reactant: O=C=O
Reactant: Fc1cc2[nH]ccc2cc1Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Temperature: -75 °C
Reaction time: 2 h

Procedure:
1.56 ml (2.49 mmol) of a 1.6 M butyl lithium solution in hexane were diluted with 3.2 ml THF at −78° C. under nitrogen. 211 mg (1.24 mmol) of 5-chloro-6-fluoro-1H-indole as a 3:1 mixture of regioisomers dissolved in 0.8 ml THF were added within 15 min keeping the temperature below −70° C. After 5 min 279 mg (2.49 mmol) of potassium-tert-butylate dissolved in 1 ml THF were added within 15 min. The reaction mixture was stirred for 2 h at −75° C. to give a clear orange solution. Solid carbon dioxide was added at that temperature and the reaction mixture was allowed to warm to rt within 30 min. Water was added and the reaction mixture was extracted twice with diethyl ether. The aqueous layer was acidified with 1N aqueous HCl solution and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was stirred with n-hexane and a trace of diethyl ether for 2 h and filtered to yield 121 mg (46 of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid as a light brown solid. 1H NMR (DMSO-d6, 300 MHz): δ 13.6 (br, 1H), 11.3 (br, 1H), 8.00 (d, 1H), 7.42 (s, 1H), 6.52 (s, 1H).
Reaction SMILES: [C:1]1(=[O:7])[CH:5]=[CH:4][C:3](=[O:6])[CH2:2]1.[CH3:8][C:9]([C:11]([CH3:13])=[CH2:12])=[CH2:10].C(C1C=C(O)C(C(C)(C)C)=CC=1O)(C)(C)C>C1C=CC=CC=1>[CH3:8][C:9]1[CH2:10][C@@H:5]2[C@H:4]([CH2:12][C:11]=1[CH3:13])[C:3](=[O:6])[CH2:2][C:1]2=[O:7]
Reactant: O=C1C=CC(=O)C1
Reactant: C=C(C)C(=C)C
Agent: CC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Solvent: c1ccccc1
Product: CC1=C(C)C[C@H]2C(=O)CC(=O)[C@H]2C1
Reaction time: 96 h

Procedure:
A solution of 4-cyclopentene-1,3-dione (5.48g; 0.06 mole) and 2,3-dimethyl butadiene (10.4g; 0.127 mole) in dry benzene (20ml) were treated with a few crystals of 2,5-di-t-butyl hydroquinone and allowed to stand at ambient temperature for 4 days. After refluxing for 15 mins the mixture was cooled and the pale orange solid filtered. Recrystallisation from benzene, methanol afforded the title product as a white solid, m.p. 157°-158° C.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[C:27]([O:31][C:32](=[O:41])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]O)([CH3:30])([CH3:29])[CH3:28]>O.ClCCl>[C:27]([O:31][C:32](=[O:41])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][I:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CCCCCCCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)CCCCCCCI
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Imidazole (2.10 g, 30.9 mmol), triphenylphosphine (8.10 g, 30.9 mmol), and iodine (6.27 g, 24.7 mmol) were successively added to a dichloromethane solution (100 mL) of t-butyl-8-hydroxyoctanoate (4) (4.45 g, 20.6 mmol) at 0° C. under the argon atmosphere, and the temperature of the reaction solution was raised to room temperature, followed by stirring for 2 hours. Thereafter, water (5 mL) was added to the reaction solution, and the mixture was washed successively with a 0.1 N aqueous sodium periodate solution (50 mL), 30% aqueous hydrogen peroxide (50 mL), and saturated brine (50 mL), dried over magnesium sulfate, and concentrated. The resulting brown oily crude product (21 g) was separated and purified by silica gel column chromatography (hexane:ethyl acetate 50:1) to obtain t-butyl-8-iodooctanoate (5) as a colorless liquid substance (5.53 g, 77%).