Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:26])[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])=[N:5]1)[CH3:3].[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:12]5[C:13](=[O:26])[C:14]6[S:18][C:17]([C:19]7[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=7)=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[N:7]=[N:8][N:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)cc6)cc5n(Cc5nnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(4-fluorophenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (108 mg; compound B82) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (88 mg; compound C10) and HBTU (183 mg) in DCM/DMF (18 ml/1 ml) in the presence of DIPEA (227 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc, 60/40 to 40/60 (v/v)] and by preparative TLC [20×20 cm TLC plates with 0.5 mm thickness, eluation gradient: EtOAc/methanol/triethylamine, 91/5/4 (v/v/v)] as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2([Cl:18])C=O)=[CH:4][CH:3]=1.N1CCCC[CH2:22]1.C(O)(=O)C.[C:31]([O:39][CH2:40][CH3:41])(=[O:38])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(O)C>[CH2:40]([O:39][C:31]([C:32](=[CH:22][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=2)[C:8]=1[Cl:18])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:38])[CH3:41]
Reactant: C1CCNCC1
Reactant: O=CC1(Cl)Cc2ccccc2N1Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1c(Cl)n(Cc2ccc(Cl)cc2)c2ccccc12)C(=O)OCC
Reaction time: 72 h

Procedure:
To 500 mg of 1-(4-Chlorobenzyl)-2-chloroindole-carbaldehyde, dissolved in 15 ml of a solvent which consisted of 5% piperidine and 2% acetic acid in absolute ethanol, was added 0.28 ml of diethyl malonate. After stirring for 3 days the solvent was removed by evaporation, and the product dissolved in 25 ml of ether plus 25 ml of 1N HCl. The organic phase was separated, and washed with 25 ml 1N HCl, 25 ml water, 25 ml of saturated NaHCO3 solution, dried (MgSO4) and evaporated to give an oil. Purification by column chromatography (methylene chloride on silica 60) gave (14a) as an oil which slowly crystallized. Yield 210 mg. M.p. 98°-99° C. (sample recryst. from EtOH/water).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:3]=1[NH2:4].[OH-].[Na+].[C:15](Cl)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].Cl>O.C(OC)(C)(C)C>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:3]=1[NH:4][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cc(N)c(Br)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: COc1cc(Br)c(NC(=O)C(C)(C)C)cc1OC
Reaction time: 1 h

Procedure:
A dry 500 mL three-necked flask was charged with 2-bromo-4,5-dimethoxyaniline (23.4 g, 0.10 mol) and t-BuOMe (200 mL), NaOH (25.3 g, 25%, 0.158 mol) was added in portions at 0° C. Then pivaloyl chloride (12.9 g, 0.106 mol) was added dropwise slowly under N2 at 0° C. After addition, the mixture was stirred for an additional 1 hour and diluted with water (100 mL), acidified by 5% HCl to pH=7 and extracted with EtOAc (100 mL×3). The combined organic layers were washed with water (100 mL×3), dried over anhydrous MgSO4, filtrated and concentrated in vacuum to afford the compound N-(2-bromo-4,5-dimethoxyphenyl)-2,2-dimethylpropanamide. MS (M+H)=316 and 318.
Reaction SMILES: C([O:9][CH:10]([C:27]([NH:29][C@@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31])=[O:28])[C@@H:11]([NH:16]C(OCC1C=CC=CC=1)=O)[CH2:12][CH2:13][CH2:14][CH3:15])(=O)C1C=CC=CC=1.[OH-].[Na+]>O1CCOCC1.O>[NH2:16][C@@H:11]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:10]([OH:9])[C:27]([NH:29][C@@H:30]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH3:31])=[O:28]
Reactant: CCCC[C@H](NC(=O)OCc1ccccc1)C(OC(=O)c1ccccc1)C(=O)N[C@H](C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCC[C@H](N)C(O)C(=O)N[C@H](C)c1ccccc1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A mixture of 8.75 g (17.4 mmol) of (2S)-2-{[(benzyloxy)carbonyl]amino}-1-({[(1R)-1-phenylethyl]amino}carbonyl)hexyl benzoate and 6.97 g (174 mmol) of sodium hydroxide in 175 mL of dioxane and 75 mL of water was heated to reflux for 3 h and then let cool to room temperature. The reaction was diluted with 100 mL of water and extracted with ethyl acetate. The combined ethyl acetate layers were dried over potassium carbonate and concentrated to afford 4.38 g (95%) of (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.08 (d, J=8 Hz, 1H), 7.39-7.20 (m, 5H), 4.99 (m, 1H), 4.51 (bs, 1H), 3.71 (d, J=3 Hz, 1H), 2.81 (m, 1H), 1.50-1.05 (m, 9H), 0.87 (t, 3H). ES-LCMS m/z 265 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH3:30])[C:21]2[C:16](=[CH:17][C:18]([CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][OH:24])=[CH:19][CH:20]=2)[O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[CH3:11][C:12]1([CH3:30])[C:21]2[C:16](=[CH:17][C:18]([CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:23]=[O:24])=[CH:19][CH:20]=2)[O:15][CH2:14][CH2:13]1
Reactant: CCCCCC(CO)c1ccc2c(c1)OCCC2(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCCC(C=O)c1ccc2c(c1)OCCC2(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 73.8 %

Procedure:
To a solution of oxalyl chloride (0.15 mL) in 9 mL of dichloromethane at −78° C. was added 0.19 mL of DMSO. The mixture was stirred at −78° C. for 5 minutes and then a solution of 2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol (0.22 g, 0.79 mmole, from Example 1) in 3 mL of dichloromethane was added. The mixture was stirred at −78° C. for 15 minutes then 0.56 mL of triethylamine was added. Stirring was continued at −78° C. for another 15 minutes then at room temperature for two hours. The reaction mixture was quenched by the addition of 20 mL of water, extracted with three 20 mL portions of dichloromethane and the combined organic extracts were washed with two 20 mL portions of water and 20 mL of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to afford 0.16 g of 2-(4,4-dimethyl-chroman-7-yl)-heptanal as a colorless oil.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([N:23]2[C:28](=[O:29])[NH:27][C:26](=[O:30])[CH:25]=[N:24]2)[CH:10]=[C:11]([Cl:22])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([N:23]2[C:28](=[O:29])[NH:27][C:26](=[O:30])[CH:25]=[N:24]2)[CH:10]=[C:11]([Cl:22])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:15]=1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.), stirred solution of chlorosulfonic acid (1 mL) was added 2-[3,5-dichloro-4-(4-methoxy-phenoxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione (0.6 g). After 30 min, the resulting brown solution was poured over ice and the resulting mixture was allowed to stir at ambient temperature for 30 min, the solids filtered and dried in vacuo to afford the title compound of Step A as a colorless solid, 0.7 g.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4CC4)=[CH:20][C:16]([C:17]([OH:19])=O)=[C:15]([F:25])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C12(COC3C(C)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.CS(N)(=O)=O.[N:54]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1>>[C:1]12([CH2:11][O:12][C:13]3[C:21]([CH3:22])=[CH:20][C:16]([C:17]([NH:61][S:58]([N:54]4[CH2:57][CH2:56][CH2:55]4)(=[O:60])=[O:59])=[O:19])=[C:15]([F:25])[CH:14]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: Cc1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Product: Cc1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2

Procedure:
Following the procedure as described in Example 50 step 5 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-2-fluoro-5-methylbenzoic acid and methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as colorless solid (0.06 g, 27%): 1H NMR (300 MHz, DMSO-d6) δ 11.59 (s, 1H), 7.48 (d, J=8.3 Hz, 1H), 6.93 (d, J=12.9 Hz, 1H), 4.04 (t, J=7.7 Hz, 4H), 3.62 (s, 2H), 2.19-2.14 (m, 5H), 1.99 (s, 3H), 1.75-1.66 (m, 12H); MS (ES+) m/z 437.2 (M+1); MS (ES−) m/z 435.2 (M−1).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:2]=1[CH:3]1[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH:4]1[CH2:5][O:6]2.[H-].[Na+].[CH:21](I)([CH3:23])[CH3:22].Cl>CN(C=O)C.O>[CH:21]([O:11][C:9]1[CH:8]=[C:7]2[C:2]([CH:3]3[O:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[CH:4]3[CH2:5][O:6]2)=[CH:1][CH:10]=1)([CH3:23])[CH3:22]
Reactant: CC(C)I
Reactant: Oc1ccc2c(c1)OCC1c3ccccc3OC21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc2c(c1)OCC1c3ccccc3OC21
Yield: 50.6 %

Procedure:
Compound 6a,11a-Dihydro-6H-benzo[4,5]furo[3,2-c]chromen-3-ol (100 mg, 0.42 mmol) was dissolved in DMF (5 ml) and NaH (10 mg, 0.42 mmol) was added to the solution at room temperature, followed by isopropyl iodide (149 mg, 0.84 mmol). The reaction mixture was stirred at room temperature to 6 hours and poured into iced water and neutralized with 10% HCl to get the white precipitate. Precipitate were washed with water and purified by silica gel column chromatography using hexane-chloroform as the eluent to give 3-isopropoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]chromene (60 mg, 51%) as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]2)[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)[CH3:2].[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:32](=[O:33])[N:31]([CH3:35])[CH3:30])[CH2:18][CH2:17]2)[C@H:22]2[CH2:23][CH2:24][C@H:25]([CH3:28])[CH2:26][CH2:27]2)=[O:14])=[N:9][CH:8]=1)[CH3:2].[CH3:30][N:31]([CH3:35])[C:32]([N:19]1[CH2:18][CH2:17][CH:16]([N:15]([C@H:22]2[CH2:23][CH2:24][C@H:25]([CH3:28])[CH2:26][CH2:27]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:29])=[CH:8][N:9]=2)[CH2:21][CH2:20]1)=[O:33]
Reactant: CN(C)C(=O)Cl
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCNCC2)[C@H]2CC[C@H](C)CC2)s1
Product: CCOC(=O)CSc1cnc(NC(=O)N(C2CCN(C(=O)N(C)C)CC2)[C@H]2CC[C@H](C)CC2)s1
Product: CN(C)C(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
{2-[3-(1-Dimethylcarbamoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester was prepared in a similar manner to Example 554 using {2-[3-(trans-4-methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester and dimethylcarbamoyl chloride. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:21])[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[CH:8][C:9]=1[Br:10])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[Br:10][C:9]1[CH:8]=[C:7]([C:11](=[O:21])[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Br
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1cccc(O)c1)c1cc(Br)c(C(=O)O)s1
Reaction time: 15 h

Procedure:
A mixture of 3-Bromo-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carboxylic acid methyl ester (160 mg, 0.43 mmol), lithium hydroxide monohydrate (180, mg, 4.32 mmol), THF (5 mL) and water (6 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 110 mg (70%). MS m/e 357.7 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.Cl.CN(C)[CH2:14][CH2:15]CN=C=NCC.C(O)C.CN(C1C=CC=CN=1)C>ClCCl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(I)nc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(I)nc1
Temperature: 50 °C

Procedure:
To a suspension of 6-iodonicotinic acid (23.38 g, 94.20 mmol) in dichloromethane (100 ml) was added a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.86 g, 103.6 mmol) in dichloromethane (250 ml). To this mixture was added ethanol (12.40 g, 269.27 mmol) followed by dimethylaminopyridine (1.15 g, 9.41 mmol). The mixture was heated at 50° C. for 24.5 hours, concentrated in vacuo, and diluted with water (200 ml) then extracted with ethyl ether (550 ml). The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO4) and concentrated to a yellow solid. Purification by flash chromatography (silica, 10% EtOAc-hexane) afforded the title compound as white needles: mp 48°-49° C.; 1H NMR (CDCl3): δ8.94 (1H, d, J=2.1 Hz), 7.91 (1dd, J=2.1, 8.2 Hz), 7.85 (1H, d, J=8.2 Hz), 4.41 (2H, q, J=7.1 Hz), 1.41 (3H, t, J=7.1 Hz).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:2]1.CN(CCN(C)C)C.C([Li])CCC.[C:27](=O)([O:30]C)[O:28][CH3:29]>C1COCC1>[CH3:29][O:28][C:27]([C:2]1[O:1][CH:5]=[CH:4][C:3]=1[NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:30]
Reactant: COC(=O)OC
Reactant: CC(C)(C)OC(=O)Nc1ccoc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1occc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of tert-butyl furan-3-ylcarbamate (1.7 g, 1.0 eq) in THF (50 ml) at −30° C. was added TMEDA (1.75 ml, 1.3 eq) followed by 1.6M solution of n-butyllithium (8.4 ml, 2.25 eq, 1.6M in hexanes). Reaction mixture was allowed to warm up to 0° C. and stirred for 1 h, before being cooled back to −30° C. Dimethyl carbonate (2.4 ml, 3.0 eq) was quickly added, before the reaction mixture was allowed to warm up to room temperature for 1 hr. Reaction mixture was quenched with 2M HCl, followed by addition of saturated aq. NaCl. Mixture was extracted with ethyl acetate. The combined organic extracts were dried with Na2SO4 and concentrated. The crude reaction mixture was purified by flash chromatography to yield tert-butyl 2-(methoxycarbonyl)furan-3-ylcarbamate (1.14 g, 51%): MS (Q1) 242 (M)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4](=[O:10])/[CH:5]=[CH:6]/[CH:7](O)[CH3:8])[CH3:2].[Cl:13]P(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[Cl:13][CH:7]([CH3:8])/[CH:6]=[CH:5]/[C:4]([N:3]([CH2:11][CH3:12])[CH2:1][CH3:2])=[O:10]
Reactant: CCN(CC)C(=O)/C=C/C(C)O
Reactant: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCN(CC)C(=O)/C=C/C(C)Cl
Temperature: 25 °C

Procedure:
To (E)-N,N-Diethyl-4-hydroxy-2-pentenamide (0.67 g, 3.93 mmol) in methylene chloride cooled to -15° C. in a flame dried flask is added dichlorotriphenylphosphorane (1.40 g, 4.33 mmol). The reaction is warmed to ambient temperature, quenched by addition of ice (10 ml), extracted with methylene chloride (3×20 ml), washed with saline (30 ml), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (75/25). The appropriate fractions are combined (Rf =0.48, TLC, hexane/ethyl acetate, 25/75) and concentrated in vacuo to give (E)-4-chloro-N,N-diethyl-2-pentenamide. 4-Amino-6-chloro-2-mercaptopyrimidine mesylate (0.56 g, 2.19 mmol) is dissolved in DMF (4 ml) and sodium hydride (0.12 g, 4.82 mmol) at ambient temperature followed by the addition of (E)-4-chloro-N,N-diethyl-2-pentenamide (0.41 g, 2.19 mmol). The reaction is stirred for 15 hours, quenched with excess water, extracted with ethyl acetate (3×25 ml). The extracts are combined, washed with saline (25 ml), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with a gradient of hexane/ethyl acetate (80/20-60/40). The appropriate fractions are combined (Rf =0.27, TLC, hexane/ethyl acetate, 25/75) and concentrated in vacuo to give the title compound, mp 152-153° C.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH:9]=[C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[CH3:21])=[O:12])[C:4]=2[N:3]=1.Cl.[NH:36]1[CH2:39][CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C>CCO>[N:36]1([C:2]2[NH:6][C:5]3[CH:7]=[C:8]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:32])([F:33])[F:34])=[O:24])[CH:9]=[C:10]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=4[CH3:21])=[O:12])[C:4]=3[N:3]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(Cl)nc12
Reactant: C1CNC1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(N3CCC3)nc12
Yield: 32.4 %

Procedure:
A solution of 2-chloro-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (80 mg, Example 135), azetidine hydrochloride (60 mg) and N,N-diisopropylethylamine (208 μL) in EtOH (1.8 mL) was reacted at 120° C. for 20 minutes in a microwave reactor (Biotage, Initiator). The reaction mixture was concentrated under reduced pressure, and the residue was purified on column chromatography to obtain 2-(azetidin-1-yl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (27 mg). This was dissolved in MeOH (1 mL), 2N hydrogen chloride/MeOH solution (1 Eq) was added, and it was stirred and concentrated. The residue was triturated in diethyl ether, and the precipitate was collected by filtration and dried to obtain the titled compound (21 mg) as white powder.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.C(N(CC)C(C)C)(C)C.Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:26]([N:8]1[CH2:7][CH:6]2[CH2:12][O:13][CH2:14][CH2:15][N:5]2[C:4]2[N:3]=[C:2]([Cl:1])[N:11]=[CH:10][C:9]1=2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Clc1ncc2c(n1)N1CCOCC1CN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48 %

Procedure:
To 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 82 mg, 0.362 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (0.076 mL, 0.434 mmol) and (bromomethyl)benzene (0.047 mL, 0.398 mmol) to give a yellow solution, which was stirred at room temperature for 48 hours. The mixture was subsequently diluted with ethyl acetate and then washed with aqueous saturated NH4Cl (2×5 mL) and brine (2×5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was loaded onto an ISCO® silica gel cartridge (4 g) and eluted using an ethyl acetatehexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow solid (55 mg, 48%). 1H NMR (400 MHz, DMSO-d6) δ 2.91-3.10 (m, 2 H), 3.10-3.22 (m, 1 H), 3.32 (s, 1 H), 3.40-3.54 (m, 1 H), 3.60-3.75 (m, 1 H), 3.81-4.01 (m, 2 H), 4.15-4.30 (m, 1 H), 4.41 (s, 2 H), 7.20-7.42 (m, 6 H). ESI-MS m/z [M+H]+ calc'd for C16H17ClN4O, 317.11; found 317.3.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17](Cl)=[O:18])=[CH:16][C:3]1=2.[NH3:20]>O1CCCC1>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([NH2:20])=[O:18])=[CH:16][C:3]1=2
Reactant: N
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1CO2
Solvent: C1CCOC1
Product: NC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The remaining half of the acid chloride IV was added to a mixture of 150 ml of concentrated ammonia and 150 ml of tetrahydrofuran. Then, the mixture was stirred at room temperature for three hours and concentrated under reduced pressure. The residue was vigorously stirred together with 300 ml of saturated aqueous solution of sodium bicarbonate and 100 ml of ether, and the solid was collected by filtration and dried to obtain 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-carboamide VIII in a quantitative yield. Recrystallization from methanol gave pure crystals having a melting point of 227°-228° C. IR spectrum (KBr tablet, cm-1): 3430, 3150, 1680, 1635, 1600, 1370.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9](=O)[C:10]1C=CC=CC=1.C(O)(=O)C1C=CC=CC=1.[CH3:26][C:27]([OH:31])(C#C)[CH3:28]>Cl[Pd]Cl.[Cu]I.C(N(CC)CC)C>[CH3:26][CH:27]([CH3:28])[OH:31].[NH2:6][C:5]1[CH:4]=[C:3]([C:9]#[CH:10])[CH:2]=[CH:8][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(Br)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: C#Cc1cccc(N)c1
Product: CC(C)O
Temperature: 50 °C

Procedure:
A mixture of 4-bromoaniline (1.72 g, 10 mmol), benzaldehyde (0.27 g free of benzoic acid, 2.5 mmol), benzoic acid (20 mg, 0.16 mmol), PdCl2 (2 mg) and triethylamine (3.5 g) was deaerated by bubbling nitrogen and then heated to reflux for 30 min. The reaction mixture was cooled to 50° C. and treated with triphenylphosphine (73 mg in 0.5 g of TEA) followed by 2-methyl-3-butyn-2-ol (1.1 g, 13 mmol) and then CuI (20 mg in 1 g TEA). This mixture was heated at reflux for 12 hr. Thin layer chromatography showed the reaction to form 3-aminophenylacetylene dimethylcarbinol, in mixture with N-benzylidene 3-aminophenylacetylene dimethylcarbinol, to be complete.