Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH3:20])[C:9]([NH:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[C:4]([C:21]([OH:23])=O)[CH:3]=1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH:24]1([NH:30][C:21]([C:4]2[CH:3]=[C:2]([Br:1])[C:7]3[N:8]([CH3:20])[C:9]([NH:11][C:12]4[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=4[Cl:18])=[N:10][C:6]=3[CH:5]=2)=[O:23])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCCCC1
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)O)cc(Br)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)NC3CCCCC3)cc(Br)c21

Procedure:
Prepared analogously to example 3c from 7-bromo-2-(2,6-dichloro-phenylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid, cyclohexylamine, TBTU and TEA in DMF.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][C:35]([N:37]2[CH2:42][CH2:41][CH2:40][C@@H:39]([C:43](=[O:58])[NH:44][C@H:45]([C:51]3[CH:52]=[N:53][CH:54]=[C:55]([OH:57])[CH:56]=3)[CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH2:38]2)=[O:36])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[F:59][C:60]1[CH:67]=[CH:66][C:65]([CH2:68]O)=[CH:64][C:61]=1[C:62]#[N:63].N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl.C1COCC1>[C:62]([C:61]1[CH:64]=[C:65]([CH:66]=[CH:67][C:60]=1[F:59])[CH2:68][O:57][C:55]1[CH:56]=[C:51]([C@@H:45]([NH:44][C:43]([C@@H:39]2[CH2:40][CH2:41][CH2:42][N:37]([C:35](=[O:36])[CH2:34][CH2:33][CH:30]3[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:26])[CH2:32][CH2:31]3)[CH2:38]2)=[O:58])[CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH:52]=[N:53][CH:54]=1)#[N:63]
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(O)c1
Reactant: N#Cc1cc(CO)ccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCc2ccc(F)c(C#N)c2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 7.8 %

Procedure:
Polymer bound triphenylphosphine (30 mg) and tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-hydroxypyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 5e, 30 mg, 60 μmol) were stirred in dichloromethane for 30 minutes. 2-Fluoro-5-(hydroxymethyl)benzonitrile (26 mg, 0.17 mmol) in THF was added and the mixture was cooled to 0° C. Dipropan-2-yl diazene-1,2-dicarboxylate (20 μL, 0.11 mmol) was added, the mixture was stirred for 3 hours at room temperature and then stored for 16 hours at 5° C. After filtration the filtrate was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography on silica gel (ethyl acetate 100%) to yield 3.2 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-1-{5-[(3-cyano-4-fluorobenzyl)oxy]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [N:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][C:10](=[O:18])[C@@H:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:12][OH:13])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH3:21]I>>[N:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][C:10](=[O:18])[C@@H:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:12][O:13][CH3:21])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: CI
Reactant: CC(=O)N[C@@H](CO)C(=O)NCc1ccc(N=[N+]=[N-])cc1
Product: COC[C@H](NC(C)=O)C(=O)NCc1ccc(N=[N+]=[N-])cc1
Yield: 81.3 %

Procedure:
Utilizing Method B, (S)—N-(4-Azidobenzyl)-2-acetamido-3-hydroxypropanamide (2.40 g, 8.66 mmol), Ag2O (10.04 g, 43.30 mmol), and MeI (5.40 mL, 86.60 mmol) gave crude (S)-5 after 4 d. The product was purified by column chromatography (SiO2; 1/9 MeOH/CHCl3) to obtain 2.05 g (81%) of (S)-5 as a white solid: mp 149-150° C.; [α]26D +15.4° (c 1.0, MeOH); Rf=0.5 (1/9 MeOH/CHCl3); IR (nujol mull) 3285, 2927, 2112, 1635, 1565, 1457 cm−1; 1H NMR (CDCl3) δ 2.03 (s, CH3C(O)), 3.38 (s, OCH3), 3.43 (dd, J=7.5, 9.0 Hz, CHH′OCH3), 3.81 (dd, J=4.2, 9.0 Hz, CHH′OCH3), 4.40 (½HH′q, J=6.0, 15.0 Hz, CHH′Ar), 4.46 (½HH′q, J=6.0, 15.0 Hz, CHH′Ar), 4.51-4.57 (m, CH), 6.43 (br d, J=6.3 Hz, NHCH), 6.78-6.83 (br m, NHCH2), 6.96-7.01 (m, 2 ArH), 7.23-7.27 (m, 2 ArH), addition of excess (R)-(−)-mandelic acid to a CDCl3 solution of (R)-5 gave only a single signal for the acetyl methyl protons and the ether methyl protons, addition of excess (R)-(−)-mandelic acid to a CDCl3 solution of (R)-5 and (S)-5 (1:2 ratio) gave two signals for the acetyl methyl protons (δ 1.995 (R) and 2.010 (S) (Δppm=0.015)), and the ether methyl protons (δ 3.302 (S) and 3.342 (R) (Δppm=0.040)); 13C NMR (CDCl3) δ 23.3 (CH3C(O)), 43.1 (CH2Ph), 52.7 (CH), 59.2 (CH2OCH3), 72.0 (CH2OCH3), 119.4, 129.1, 135.0, 139.4 (C6H5), 170.3, 170.6 (2 C(O)); HRMS (ESI) 292.1405 [M+H+] (calcd. for C13H18N5O3 292.1410); Anal. (C13H17N5O3) Calcd.: C, 53.60%; H, 5.88%; N, 24.04%. Found: C, 53.76%; H, 5.97%; N, 24.22%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13][CH3:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[N:30]1[CH2:36][CH2:35][CH2:34][N:33]([CH2:37][CH2:38][C:39]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:32][CH2:31]1)[CH3:17]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13][CH3:14])=[CH:8][C:4]=1[C:5]([N:41]1[CH2:42][CH2:43][C:39]([CH2:38][CH2:37][N:33]2[CH2:34][CH2:35][CH2:36][N:30]([C:22]3[N:21]([CH2:20][CH2:19][O:18][CH2:16][CH3:17])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=3)[CH2:31][CH2:32]2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:7]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(CSC)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(CSC)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-(methylthiomethyl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[O:6].C([O:26][C:27](=[O:40])[CH2:28][CH2:29][C:30]1[CH:35]=[C:34]([Cl:36])[C:33]([CH:37]=O)=[C:32]([Cl:39])[CH:31]=1)(C)(C)C>>[Cl:36][C:34]1[CH:35]=[C:30]([CH2:29][CH2:28][C:27]([OH:40])=[O:26])[CH:31]=[C:32]([Cl:39])[C:33]=1[C:37]1[NH:1][C:2]2[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]3[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=3)[CH:18]=[CH:19][C:20]=2[N:21]=1
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(C=O)c(Cl)c1
Reactant: Nc1ccc(C(=O)Nc2ccc(C(F)(F)F)nc2)cc1N
Product: O=C(O)CCc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc(C(F)(F)F)nc4)cc3[nH]2)c(Cl)c1

Procedure:
The title compound was prepared from 3,4-diamino-N-(6-trifluoromethylpyridin-3-yl)-benzamide (from Example 6-36) and 3-(3,5-dichloro-4-formylphenyl)-propionic acid tert butyl ester analogous to Example 6-25. 1H NMR (MeOD, 400 MHz): δ 9.07 (d, 1H), 8.54 (dd, 1H), 8.35 (s, 1H), 7.99 (dd, 1H), 7.84 (dd, 1H), 7.76 (d, 1H), 7.52 (s, 2H), 3.01 (t, 2H), 2.69 (t, 2H); MS (m/z) 523.01 (M+1), Retention time=1.06 min (Method 10).
Reaction SMILES: [Mg].Br[C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH3:11])[C:6]([O:12][CH3:13])=[CH:5][CH:4]=1.C[Mg]Br.[C:17](=[O:19])=[O:18].Cl>O1CCCC1.O>[CH3:11][O:10][C:7]1[C:8]([CH3:9])=[C:3]([CH:4]=[CH:5][C:6]=1[O:12][CH3:13])[C:17]([OH:19])=[O:18]
Reactant: COc1ccc(Br)c(C)c1OC
Reactant: O=C=O
Agent: C[Mg]Br
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(C)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a mixture of magnesium turnings (0.059 g, 2.40 mmol) in tetrahydrofuran (1 ml) was added a solution of 6-bromo-2,3-dimethoxy toluene (0.660 g, 2.3 mmol) in tetrahydrofuran (1 ml). The reaction was initiated by addition of methylmagnesium bromide and the solution was stirred at room temperature overnight under nitrogen. To the mixture was then added an excess of dry ice. When the addition was complete, water was added (2 ml) followed by 1.5 M hydrochloric acid to pH 2. The water phase was extracted with ethyl acetate (2×5 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated to give 3,4-dimethoxy-2-methylbenzoic acid (0.315 g, 70% yield). MS (EI) for C10H12O4: 195 (M−H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:24][CH3:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:16]=1)#[CH:10]>C1COCC1.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.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:12]=[CH:13][C:14]([O:24][CH3:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccc(OC)c(NC(=O)C(F)(F)F)c1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COc1ccc(C#Cc2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Yield: 83.1 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloropyrimidine (860 mg, 5.76 mmol), anhydrous degassed THF (100 mL), dichlorobis(triphenylphosphine)-palladium(II) (81 mg, 0.12 mmol), copper(I) iodide (13 mg, 0.07 mmol), and TEA (1.26 g, 0.013 mol). After heating the reaction at 60° C. for 30 min, N-[5-ethynyl-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (560 mg, 2.30 mmol) was added dropwise as a solution in THF (10 mL) and the resulting mixture was allowed to heat overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (0-10% EtOAc in hexanes) to afford the desired product (0.68 g, 42%) as an off white solid. ES-LC/MS m/z=356 [M+H]+.
Reaction SMILES: [Li+:1].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)(=[O:13])[CH3:12].[C:19](OC(C)(C)C)(=[O:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CCOCC>[C:23]([O:22][C:20](=[O:21])[C:19]([O-:27])=[CH:12][C:11]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)=[O:13])([CH3:26])([CH3:25])[CH3:24].[Li+:1]
Reactant: CC(=O)c1ccco1
Reactant: CC(C)(C)OC(=O)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C([O-])=CC(=O)c1ccco1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
A 1-L flame-dried flask was charged with 130 mL of LiHMDS (130 mmol; 1.0 M in THF) and 410 mL of ethyl ether. The resulting solution was cooled to −78° C. and 2-acetylfuran (14 g, 12 m mmol) was added in one portion. After 5 min, di-tert-butyl oxalate was added dropwise over 1 h as a solution in 100 mL of ether. The resulting mixture was warmed to 23° C. over a period of 3 h and was maintained at rt for 20 h. The mixture was then filtered, and the resulting beige precipitate was washed with 100 mL of ether. The filter cake was dried in a vacuum oven for 1 h to afford lithium 1-tert-butoxy-4-(2-furyl)-1,4-dioxo-2-buten-2-olate (25 g, 83%) as a cream colored solid. 1H NMR (DMSO-d6) δ 7.75 (t, 1H), 6.96 (m, 1H), 6.56 (m, 1H), 3.34 (s, 2H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:18]([CH3:19])[C:17]3[C:12](=[N:13][C:14]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:15][CH:16]=3)[N:11]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:10]2=[O:33])=[CH:5][CH:4]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:18]([CH3:19])[C:17]3[CH:16]=[N:15][C:14]([N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:34](=[O:36])[CH3:35])=[N:13][C:12]=3[N:11]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:10]2=[O:33])=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N2C(=O)N(c3ccccc3)c3nc(Nc4ccccc4)ncc3C2C)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(N2C(=O)N(c3ccccc3)c3nc(N(C(C)=O)c4ccccc4)ncc3C2C)cc1
Temperature: 90 °C

Procedure:
To a suspension of (±)-3-(4-methoxy-phenyl)-4-methyl-1-phenyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (500 mg, 1.14 mmol) (from Example 1g supra) in pyridine (1 mL) (Fisher) was added acetic anhydride (1.0 mL) followed by addition of 4-(dimethylamino)pyridine (25 mg) (Aldrich) in one portion. The reaction mixture was heated to 90° C. for 5 hours until no starting material was detectable by TLC analysis. The reaction mixture was quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product which was purified by flash chromatography to give (±)-N-[6-(4-methoxy-phenyl)-5-methyl-7-oxo-8-phenyl-5,6,7,8-tetrahydro-pyrimido[4,5-d]pyrimidin-2-yl]-N-phenyl-acetamide. (Yield 373 mg, 68.0%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[S:24][C:23]3[C:18](=[N:19][C:20]([Cl:25])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:26])#[N:2].CI.[H-].[Na+].[CH3:34]COC(C)=O>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH3:34])[S:13]([C:16]2[S:24][C:23]3[C:18](=[N:19][C:20]([Cl:25])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:26])#[N:2]
Reactant: CCOC(C)=O
Reactant: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3cc4nc(Cl)ccc4s3)C2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN([C@H]1CCN(Cc2cccc(C#N)c2)C1=O)S(=O)(=O)c1cc2nc(Cl)ccc2s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5-Chlorothieno[3,2-b]pyridine-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide (0.25 g, 0.56 mmol) is dissolved in 6 mL of DMF and cooled to 0° C. To the solution is added methyl iodide (0.40 g, 2.82 mmol) and sodium hydride (25 mg of a 60% dispersion in mineral oil, 0.62 mmol). The reaction mixture is allowed to warm to room temperature and is stirred for 2 h. At this time, the solution is diluted with and EtOAc and the layers are separated. The organic layer is washed with 1N HCl, H2O, saturated NaHCO3 solution and saturated NaCl. The organic phase is then dried over MgSO4, filtered and concentrated to give the title compound (0.25 g, 0.54 mmol) as a solid.
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:5][CH2:4][CH2:3]1.S(=O)(=O)(O)O.[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH3:22])[CH:21]=1)[NH:18][N:17]=[CH:16]2.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:12][C:13]1[CH:21]=[C:20]([CH3:22])[C:19]2[C:15](=[CH:16][N:17]([C:2]3([CH3:1])[CH2:5][CH2:4][CH2:3]3)[N:18]=2)[CH:14]=1
Reactant: Cc1cc(Br)cc2cn[nH]c12
Reactant: CC1(O)CCC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc2cn(C3(C)CCC3)nc12

Procedure:
1-Methyl-1-cyclobutanol (3 mL) and concentrated sulfuric acid (0.1 mL) were added to 5-bromo-7-methyl-1H-indazole (633 mg). The reaction solution was allowed to react in a microwave reactor at 100° C. for 30 minutes, and then further allowed to react at 120° C. for 30 minutes. An aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution. After separation, the organic layer was washed with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum, and the resultant was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 5-bromo-7-methyl-2-(1-methylcyclobutyl)-2H-indazole.
Reaction SMILES: C(=O)(O)[O-].[Na+].Br[CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]1.[O:14]=[C:15]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[NH:18][CH2:17][CH:16]1[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>CN(C)C=O>[O:14]=[C:15]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]([CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]2)[CH2:17][CH:16]1[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: BrC1C=CCCCC1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(C2C=CCCCC2)c2ccccc2NC1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
Sodium bicarbonate (1.6 g) and 3-bromocycloheptene (3.33 g) were added to a solution of 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.77 g) in N,N-dimethylformamide (20 ml), the mixture was stirred at 50° C. for one hour. After the reaction mixture was allowed to cool, ice-water was added thereto, extracted with ethyl acetate, the organic layer was washed with saturated brine. The resultant mixture was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(ethyl acetate:n-hexane=1:2), diisopropyl ether was added to the residue for crystallization, and collected by filtration, to thereby obtain 2.1 g of the title compound as the mixture of diastereomer compounds.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:8]=2)[NH:3]1.[CH:20]([C:22]1[NH:26][C:25]([CH3:27])=[C:24]([C:28]([OH:30])=[O:29])[C:23]=1[CH3:31])=O>C(O)C.N1CCCCC1>[C:12]([NH:11][C:6]1[CH:5]=[C:4]2[C:9]([C:10](=[CH:20][C:22]3[NH:26][C:25]([CH3:27])=[C:24]([C:28]([OH:30])=[O:29])[C:23]=3[CH3:31])[C:2](=[O:1])[NH:3]2)=[CH:8][CH:7]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1Cc2ccc(NC(=O)c3ccccc3)cc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(NC(=O)c4ccccc4)ccc32)c(C)c1C(=O)O
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of N-(2-oxo-2,3-dihydro-1H-indol-6-yl)-benzamide (80 mg, 0.32 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (53 mg, 0.32 mmol) in ethanol (8 ml) is added 4 drops of piperidine. It is stirred at 80° C. for 20 hours and then cooled to room temperature. The precipitate is collected by vacuum filtration, washed with a small amount of cold ethanol to give crude 5-(6-benzoylamino-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid. This carboxylic acid (20 mg, 0.050 mmol) is then dissolved in DMF (1 ml). To this reaction is also added N, N-diethylethylenediamine (17 mg, 0.15 mmol), N,N-diisopropylethylamine (19 mg, 0.15 mmol) and HATU (23 mg, 0.061 mmol). It is stirred for 2 hours and concentrated. The desired compound is obtained after HPLC purification: 1H NMR (DMSO-d6) δ 1.24 (t, 6H, J=7.2 Hz), 2.43 (s, 3H), 2.47 (s, 3H), 3.20-3.24 (m, 6H), 3.57 (q, 2H, J=5.4 Hz), 7.38 (d, 1H, J=6.6 Hz), 7.53 (t, 2H, J=7.2 Hz), 7.56 (s, 1H), 7.58-7.61 (m, 2H), 7.73-7.77 (m, 2H), 7.96 (d, 2H, J=7.8 Hz), 9.32 (s, 1H), 10.27 (s, 1H), 10.97 (s, 1H), 13.60 (s, 1H); LC-MS: 500.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CCOC(=O)C(N)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccncc1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(4-pyridyl)acetate hydrochloride (prepared as described in P. Kolar et al., J. Heterocyclic Chem., 28, 1715 (1991) and references cited therein), the title compound was prepared as a solid (mp=175-181° C.). The reaction was monitored by tlc (Rf=0.1 in 98:2 CHCl3/MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl3/MeOH as the eluent, followed by recrystallization from chlorobutane.
Reaction SMILES: [C:1]1(=O)[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3.[NH2:16][NH2:17]>CN(C=O)C.C(O)C>[N:16](=[C:1]1[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3)[NH2:17]
Reactant: O=C1Nc2ccc3ncccc3c2C1=O
Reactant: NN
Solvent: CN(C)C=O
Solvent: CCO
Product: NN=C1C(=O)Nc2ccc3ncccc3c21
Temperature: 25 °C
Yield: 70.7 %

Procedure:
A solution of 2.3 g (12 mmol) of 3-H-pyrrolo[3,2-f]quinoline-1,2-dione and 2.0 ml (0.06 mol) of hydrazine in 50 ml of DMF and 50 ml of ethanol was stirred at reflux for 2 h. The resulting suspension was allowed to cool to ambient temperature and was then chilled in an ice bath and filtered. The solid was washed with a small volume of ethanol and allowed to air dry to give 1-hydrazono-1,3-dihydropyrrolo[3,2-f]quinolin-2-one as an orange solid (1.8 g, 73%): 1H NMR (DMSO-d6): δ7.37 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.4, 4.2 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 8.71 (dd, J=4.2, 1.6 Hz, 1H), 8.80 (d, J=8.4 Hz, 1H), 9.90 (br d, J=14.7 Hz, 1H), 10.89 (br d, J=14.7 Hz, 1H), 10.95 (br s, 1H); ESI−MS m/z 213 (M+H)+. A solution 1.8 g (8.5 mmol) of 1-hydrazono-1,3-dihydropyrrolo[3,2-f]quinolin-2-one in 50 ml of freshly prepared 0.5 M sodium ethoxide solution was stirred at reflux for 3 h. The solution was diluted with 50 ml of water, neutralized with acetic acid, and concentrated on a rotary evaporator until cloudy. The solution was stored in a refrigerator overnight. The solid was filtered off, and the filtrate was extracted with three 80-ml portions of EtOAc. A solution of the solid in MeOH/EtOAc was combined with the extracts and passed through a short pad of silica gel, eluting with EtOAc. The solution was then concentrated to a small volume on a rotary evaporator, and the resulting suspension was diluted with an equal volume of ethanol, sonicated, and filtered to give 3-H-pyrrolo[3,2-f]quinoline-2-one as a light green solid (0.52 g, 33%); 1H NMR (DMSO-d6): δ3.80 (s, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.4, 4.2 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.70 (dd, J=4.2, 1.6 Hz, 1H), 10.57 (br s, 1H); APCI−MS m/z 183 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[C:13]1([CH:19]([O:21][C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:26][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:20])=[CH:28][CH:27]=1)=[O:8])=[O:5]
Reactant: CC(Oc1ccc(N)cc1)c1ccccc1
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: CC#N
Product: CC(Oc1ccc(NC(=O)NC(=O)c2ccccc2Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
18.7 g of 2-chlorobenzoylisocyanate were added to 150 ml of a solution of 23.4 g of 4-(1-phenylethoxy)aniline in dry acetonitrile. After stirring at room temperature for a few hours, the crystalline precipitate was sucked off, washed with successively acetonitrile, ethanol and petroleum ether and dried in air. The desired product was obtained in a yield of 32.8 g; melting point 166°-167° C. The starting aniline was obtained from the corresponding nitro compound by hydrogenation with hydrogen under the influence of Raney nickel as a catalyst in alcohol as a solvent. α-Methylbenzyl-4-nitrophenyl ether was prepared from a reaction of 1-bromo-1-phenyl-ethane and 4-nitrophenol under the influence of anhydrous potassium carbonate in acetone as a solvent.