Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C(Cl)CCl.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][CH:29]([C:32]([N:42]6[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]6)=[O:33])[CH2:28][CH2:27]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C(O)C1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Reactant: C1CNCCN1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(C1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.9 %

Procedure:
A mixture of crude 1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-piperidine-4-carboxylic acid (75 mg, 0.15 mmole), EDC (72 mg, 0.376 mmole), and DMAP (37 mg, 0.3 mmole) in dry DCM (1 mL) was stirred at RT for 0.5 hr. Piperazine (104 mg, 1.2 mmole) was added and, after 64 hr, the reaction was diluted with DCM, washed with water and dried (Na2SO4). Removal of solvent followed by radial chromatography (1 mm silica gel plate, gradient elution with DCM containing 1 to 5% MeOH) afforded the title compound as a solid (11 mg, 13%). 1H NMR (CDCl3) δ 1.67-1.80 (m, 4H), 1.96-2.09 (m, 2H), 2.15-2.18 (m, 1H), 2.58-2.65 (m, 1H), 2.82-2.86 (m, 4H), 3.17-3.20 (m, 2H), 3.43-3.48 (m, 2H), 3.57-3.62 (m, 2H), 3.77 (s, 2H), 5.57 (s, 2H), 6.48 (d, 1H, J=2.5 Hz), 6.83-6.88 (m, 1H), 6.90-6.97 (m, 2H), 7.21-7.29 (m, 1H), 7.36-7.39 (m, 1H), 7.44 (d, 1H, J=2.7 Hz), 7.55-7.58 (m, 1H), 7.89 (s, 1H), 8.08 (s, 1H), 8.18 (d, 1H, J=1.5 Hz), 11.87 (br, 1H). MS: 568.67 (M+H+); HPLC Ret Time: 1.03 min (Gradient Time=2 min, Flow Rate=5 ml/min, Xterra 3.0×50 mm S7 C18 column).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[C:7]1([C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:17])[C:14](O)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C)C=O.ClCCl>[C:7]1([C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:17])[C:14]([Cl:4])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C(=O)Cl)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
52.08 g (0.33 mol) of oxalyl chloride are slowly added dropwise to a suspension of 25.0 g (0.11 mol) of 2,2-diphenylpropionic acid, 100 mL of dichloromethane, and 4 drops of dimethylformamide at 20° C. The mixture is stirred for 1 hour at 20° C. and 0.5 hours at 50° C. The solvent is distilled off and the residue remaining is used in the next step without any further purification.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[C:40]1(B2OC(C)(C)C(C)(C)O2)[CH2:44][CH2:43][CH2:42][CH:41]=1>>[NH2:32][C:4]1[S:3][C:2]([C:40]2[CH2:44][CH2:43][CH2:42][CH:41]=2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(C3=CCCC3)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane gave 271. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.80 (s, 1H), 7.35 (br, J=8.5 Hz, 2H), 6.21-6.14 (m, 1H), 5.22-4.76 (m, 2H), 4.22-3.94 (m, 2H), 3.71 (s, 3H), 3.53-3.40 (m, 1H), 2.76-2.66 (m, 2H), 2.22-2.10 (m, 1H), 2.02-1.87 (m, 3H), 1.84-1.67 (m, 2H). LCMS (ES+) m/z 421 (M+1).
Reaction SMILES: [O:1]([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][OH:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=1>>[O:1]([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][O:23][CH2:31][C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccncc1
Reactant: OCCn1cnc2c(Oc3ccccc3)nc3ccccc3c21
Agent: Cl
Product: c1ccc(Oc2nc3ccccc3c3c2ncn3CCOCc2ccncc2)cc1
Yield: 21 %

Procedure:
Using the general method of Example 13 Part F, 2-(4-phenoxy-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (1.1 g, 3.61 mmol) was reacted with 4-picolyl chloride hydrogen chloride (0.649 g, 3.96 mmol) and the product purified to provide ˜0.3 g of 4-phenoxy-1-[2-(pyridin-4-ylmethoxy)ethyl]-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: C([NH:4][C:5](C(OCC)=O)([CH2:11]/[CH:12]=[CH:13]/[CH2:14][N:15]1C(=O)C2=CC=CC=C2C1=O)[C:6]([O:8]CC)=[O:7])(=O)C.[ClH:31]>>[ClH:31].[ClH:31].[NH2:4][CH:5]([CH2:11]/[CH:12]=[CH:13]/[CH2:14][NH2:15])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(C/C=C/CN1C(=O)c2ccccc2C1=O)(NC(C)=O)C(=O)OCC
Agent: Cl
Product: NC/C=C/CC(N)C(=O)O
Reaction time: 20 h

Procedure:
Ex-7c) A mixture of 25 g ethyl trans-2-acetamido-2-carbethoxy-6-phthalimido-4-hexenoate and 200 mL 37% HCl is heated under reflux for 20 h and then left at 0-2° C. for 20 h. It is then filtered to remove phthalic acid and the filtrate is reduced to dryness in vacuo. 100 mL of absolute ethanol is then added and evaporated under vacuum. Residual solid is taken up in 100 mL absolute ethanol and filtered to give 13 g of trans-2,6-Diamino-4-hexenoic acid dihydrochloride.
Reaction SMILES: [CH2:1]([C:8]1[C:9]2[CH2:32][NH:31][CH2:30][CH2:29][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:17]([O:27][CH3:28])[CH:16]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH2:1]([C:8]1[C:9]2[CH2:32][N:31]([CH3:33])[CH2:30][CH2:29][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:17]([O:27][CH3:28])[CH:16]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CNCC3)ccc1-n1cnc(C)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CN(C)CC3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.9 %

Procedure:
4-Benzyl-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (400 mg, 0.94 mmol, example 106) was is dissolved in methanol (5 mL). Acetic acid (0.054 mL, 0.94 mmol) was added followed by formaldehyde (0.070 mL, 0.94 mmol). The reaction mixture was stirred at room temperature for 15 minutes and sodium cyanoborohydride (58.9 mg, 0.94 mmol) was added. LCMS analysis showed full conversion after 1 h. The solvent was evaporated under reduced pressure, the crude redissolved in methanol, filtered and purified by preparative HPLC yielding 4-benzyl-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (74.0 mg, 17.60%). MS (ES+) m/z 441.3 (M+H)+
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][C:18](O)=O)[CH2:6]1)(=[O:3])[CH3:2].S(Cl)([Cl:33])=O>C1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][CH2:18][Cl:33])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1
Solvent: c1ccccc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCCl)[C@@]4(C)CC[C@@H]32)C1

Procedure:
3β-Acetoxychol-5-enic acid (500 g; 1.2 moles) was added to 8 liters of anhydrous benzene obtained by dehydration with a molecular sieve. The resulting solution was cooled with ice, and with stirring, 390 ml (5.4 moles) of thionyl chloride was added dropwise. After the addition, the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and 2 liters of anhydrous benzene resulting from dehydration with a molecular sieve was added to the residue. The mixture was repeatedly concentrated under reduced pressure (five times) to remove the thionyl chloride contained in the residue. The resulting solid crude product, 3β-acetoxychol-5-enyl chloride, was used in the subsequent step as a starting compound without purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[C:17]([O:21][C:22]([NH:24][C@H:25]([CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[CH2:26][C:27](O)=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:27](=[O:28])[CH2:26][C@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=3)[CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Reactant: Cc1nc2ccccc2n1C1CCCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1C1CCCN(C(=O)C[C@@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)C1

Procedure:
(2-methyl-1-(piperidin-3-yl)-1H-benzo[d]imidazole (0.486 mmoles, 0.160 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. DMF (4 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.486 mmoles, 0.140 g) and N-methylmorpholine (1.94 mmoles, 0.214 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.534 mmoles, 0.204 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (35-95% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording (R)-tert-butyl 4-(3-(2-methyl-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (1354) as a clear oil. ESI-MS: raiz 527.5 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[C:20]1([C:19]2[N:5]3[C:6]4[CH:18]=[CH:17][CH:16]=[N:15][C:7]=4[NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:4]3=[N:3][C:2]=2[C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1ccncc1
Reactant: Brc1nc2n(c1-c1ccccc1)-c1cccnc1Nc1ccccc1-2
Product: c1ccc(-c2c(-c3ccncc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1

Procedure:
The title compound was synthesized according to the procedure described in step 1 of example 19 using 2-bromo-3-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine and pyridin-4-ylboronic acid. 1HNMR (CDCl3) 400 MHz δ: 8.50-8.47 (m, 2H), 8.18-8.14 (m, 1H), 8.06-8.03 (m, 1H), 7.49-7.46 (m, 2H), 7.44-7.31 (m, 5H), 7.29-7.22 (m, 1H), 7.20-7.16 (m, 1H), 6.98-6.94 (m, 1H), 6.83-6.78 (m, 1H), 6.64 (dd, J=8.0, 4.6 Hz, 1H), 6.28 (br s, 1H); LC/MS: 388 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1Nc1cncc(F)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cccc(Br)c1Nc1cncc(F)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of N-(2-bromo-6-nitrophenyl)-5-fluoropyridin-3-amine (5.686 g, 18.22 mmol) and tin(II) chloride dihydrate (20.56 g, 91 mmol) in EtOAc (121 mL) was heated under reflux with stirring. After 2.5 h, the mixture was cooled to rt. The cooled mixture was poured into 10M aqueous NaOH solution (150 mL). The mixture was extracted with EtOAC (100 mL×2) washed with water (100 mL×2), brine (100 mL×1), dried over Mg2SO4, filtered, and concentrated in vacuo. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep™ pre-packed silica gel column (120 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide 6-bromo-N1-(5-fluoropyridin-3-yl)benzene-1,2-diamine as brown syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.84 (1H, s), 7.76-7.82 (2H, m), 6.91-6.98 (1H, m), 6.81-6.87 (1H, m), 6.77 (1H, dd, J=8.0, 1.4 Hz), 6.39 (1H, dt, J=11.7, 2.3 Hz), 5.28 (2H, s); LC-MS (ESI) m/z 282.0 [M+H (79Br)]+ and 283.9 [M+H (81Br)]−.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.C([O-])([O-])=O.[K+].[K+]>>[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][N:10]([CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[C:12]([Br:11])[CH:13]=1)[C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1cccc(CN(Cc2cccc(Br)c2)c2ccc3[nH]cnc3c2)c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 3-bromobenzylbromide (550 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.227 g (48.2%); MS m/z: 470.1/472.2/474.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.70 (s, 4H); 6.68-6.70 (m, 2H); 7.26-7.27 (m, 4H); 7.34 (d, 1H, 3J=8.6 Hz); 7.39-7.41 (m, 2H); 7.43 (s, 2H); 7.91 (s, 1H); 11.93 (br s, 1H); HPLC (METHOD [A]): rt 17.81 min (98.3%)
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]#[N:9].S(=O)(=O)(O)[OH:11]>>[NH2:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]([NH2:9])=[O:11]
Reactant: O=S(=O)(O)O
Reactant: Cn1cnc(C#N)c1N
Product: Cn1cnc(C(N)=O)c1N

Procedure:
The cyano group of 5-amino-1-methyl-1H-imidazole-4-carbonitrile 1 is hydrolyzed with sulfuric acid to give 5-amino-1-methyl-1H-imidazole-4-carboxamide 2. Cyclization with urea gives 9-methyl-1H-purine-2,6(3H,9H)-dione 3. Chlorination with phosphorus pentachloride and phosphorusoxychloride gives 2,6-dichloro-9-methyl-9H-purine 4 (CAS Registry 2382-10-7).
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:25][CH2:24][C:5]2([CH2:9][N:8]([C:10](=[O:20])[C@H:11]([CH:17]([CH3:19])[CH3:18])[NH:12][C:13]([O:15][CH3:16])=[O:14])[C@H:7]([C:21]([OH:23])=[O:22])[CH2:6]2)[CH2:4][CH2:3]1.[CH3:27][O:28][C:29]([NH:31][C@H:32]([C:36]([N:38]1[CH2:64][CH2:63][CH2:62][C@H:39]1[C:40]([O:42][CH2:43][C:44]([C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:61])[CH2:59]Br)=[CH:54][CH:53]=2)=[CH:48][CH:47]=1)=[O:45])=[O:41])=[O:37])[CH:33]([CH3:35])[CH3:34])=[O:30].C(N(CC)CC)C>C(#N)C>[F:26][C:2]1([F:1])[CH2:25][CH2:24][C:5]2([CH2:9][N:8]([C:10](=[O:20])[C@@H:11]([NH:12][C:13]([O:15][CH3:16])=[O:14])[CH:17]([CH3:19])[CH3:18])[C@H:7]([C:21]([O:23][CH2:59][C:58]([C:55]3[CH:56]=[CH:57][C:52]([C:49]4[CH:48]=[CH:47][C:46]([C:44](=[O:45])[CH2:43][O:42][C:40]([C@@H:39]5[CH2:62][CH2:63][CH2:64][N:38]5[C:36](=[O:37])[C@@H:32]([NH:31][C:29]([O:28][CH3:27])=[O:30])[CH:33]([CH3:35])[CH3:34])=[O:41])=[CH:51][CH:50]=4)=[CH:53][CH:54]=3)=[O:61])=[O:22])[CH2:6]2)[CH2:4][CH2:3]1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCC(F)(F)CC2)C[C@H]1C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCC(=O)c1ccc(-c2ccc(C(=O)CBr)cc2)cc1)C(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCC(=O)c1ccc(-c2ccc(C(=O)COC(=O)[C@@H]3CC4(CCC(F)(F)CC4)CN3C(=O)[C@@H](NC(=O)OC)C(C)C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3S)-8,8-difluoro-2-{N-[(methyloxy)carbonyl]-L-valyl}-2-azaspiro[4.5]decane-3-carboxylic acid (116) (168 mg, 0.45 mmol) and 2-[4′-(bromoacetyl)-4-biphenylyl]-2-oxoethyl N-[(methyloxy)carbonyl]-L-valyl-L-prolinate (70) (250 mg, 0.43 mmol) in anhydrous acetonitrile (2 mL) was added triethylamine (0.09 mL, 0.64 mmol) and the reaction stirred at room temperature under nitrogen for 1 h. The reaction was partitioned between EtOAc and 0.1 N HCl (30 mL each), the organic layer was washed with brine and dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 65-100% hexanes/EtOAc to afford the title compound as an off white solid (309 mg, 82% yield).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:15]([O:13][C:12](=[O:14])[C@H:9]([CH2:10][OH:11])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
In a round-bottomed flask were placed N-BocSerine (20.0 g, 89.605 mmol, 1 eq.), benzyl bromide (10.76 ml, 90.50 mmol, 1.01 eq.) and cesium carbonate (56.64 g, 173.84 mmol, 1.94 eq.) in DMF (180 mL). The suspension was stirred under nitrogen at room temperature for 2 hrs to overnight. The mixture was partitioned between water and ethyl acetate (1:1, 1000 ml) and aqueous layer was re-extracted with ethyl acetate(2×200 mL). The combined organic layers were washed with water (2×500 mL), saturated sodium chloride, and dried over sodium sulfate. The solvents were removed in vacuo and the crude material purified on silica gel to get N-Boc-serine benzyl ester.
Reaction SMILES: CCCC[Sn]([O:14][Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])(CCCC)CCCC.O[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.O>C1C=CC=CC=1>[CH2:24]([Sn:15]([O:14][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Reactant: OCCc1ccccn1
Solvent: O
Solvent: c1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)OCCc1ccccn1

Procedure:
2-(2-Pyridyl)ethyl Tributylstannyl Ether is prepared from 59.6 gm (0.1 mole) of bis(tributyltin) oxide and 24.6 gm (0.2 mole) 2-(β-hydroxyethyl)pyridine in 200 ml benzene. This is stirred and heated to reflux in a system that contains a Dean-Starke tube. After 30 minutes refluxing water began to collect in the Dean-Starke tube and after refluxing 22 hours a total of 2.0 ml of water (theory 1.8 ml) had collected. This is evaporated on a rotating evaporator to provide 82.6 gm of straw colored liquid, which fractionated at reduced pressure. 66.4 gm. of a straw colored liquid are collected at 155°-158° C. at 0.5 mm. (Percent yield - 80.6). Infrared spectral analysis shows this to be the desired ether.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=2.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][C:8]([CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=3)[CH:19]=[N:18]1
Reactant: O=C(O)Cc1ccc2ncc(Br)cc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cnc3ccc(CC(=O)O)cc3c2)cn1
Temperature: 130 °C

Procedure:
To a 20 mL microwave vial was added (3-bromo-quinolin-6-yl)-acetic acid (1 g, 3.77 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester and 1,4-dioxane (10 mL). Nitrogen was bubbled through the mixture for 10 minutes. Potassium carbonate (1.56 g, 11.3 mmol) was and water (5 mL) were then added, and nitrogen was bubbled through the mixture for a further three minutes. After such time dichlorobis(triphenylphosphine)palladium (138 mg, 0.19 mmol) was added, the vial sealed and heated in a microwave for 1250 seconds at 130° C. The mixture was then filtered through celite, which was washed with water and saturated aqueous sodium bicarbonate. The 1,4-dioxane in the solution was removed under vacuum and the remaining aqueous solution washed with dichloromethane three times. The water layer was acidified to pH 6 using 4M hydrochloric acid and the formed precipitate collected via filtration and dried to return the title compound as an off white solid. (500 MHz, DMSO-d6): ES-MS m/z: 268 (M+H+).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:29])[N:11]([CH3:28])[CH:12]=[N:13][C:14]=1[C:15]1[O:16][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[N:18][N:19]=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:17]2[O:16][C:15]([C:14]3[N:13]=[CH:12][N:11]([CH3:28])[C:10](=[O:29])[C:9]=3[OH:8])=[N:19][N:18]=2)=[CH:26][CH:25]=1
Reactant: Cn1cnc(-c2nnc(Cc3ccc(F)cc3)o2)c(OCc2ccccc2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cnc(-c2nnc(Cc3ccc(F)cc3)o2)c(O)c1=O

Procedure:
Reaction of 5-benzyloxy-6-[5-(4-fluoro-benzyl)-[1,3,4]oxadiazol-2-yl]-3-methyl-3H-pyrimidin-4-one and a 1:1 mixture of TFA/CH2Cl2 gave the debenzylated product in reasonable yield. Results are summarized below.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-:20])=[C:4]2[CH2:8][CH2:9][C@@H:10]([CH3:11])[C:3]=12
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@@H]1CCc2c1c(Cl)nc[n+]2[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.1 %

Procedure:
To a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (2.5 g, 14.8 mmol) in CHCl3 (60 mL) was added MCPBA (8.30 g, 37.0 mmol) in three portions. The mixture was stirred at room temperature for 2 days. The mixture was cooled to 0° C. and to this was added dropwise Na2S2O3 (10 g) in water (60 mL), followed by Na2CO3 (6 g) in water (20 mL). The reaction mixture was stirred for 20 minutes. The aqueous phase was extracted with CHCl3 (2×200 mL), and the combined organic phases were concentrated at low temperature (<25° C.). The residue was purified by silica gel chromatography, eluting with ethyl acetate-DCM/MeOH (20:1) to give (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-oxide (1.45 g, 53%). 1H NMR (CDCl3, 400 MHz) δ 8.66 (s, 1H), 3.50 (m, 1H), 3.20 (m, 2H), 2.44 (m, 1H), 1.90 (m, 1H), 1.37 (d, J=7.2 Hz, 3H).