Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[NH2:18][C@@:19]1([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[Cl:11][C:6]1[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=[C:2]([NH:18][C@@:19]2([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]2)[C:7]=1[CH2:8][CH2:9][OH:10]
Reactant: OCCc1c(Cl)nc(N2CCOCC2)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@](C)(N)C1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@](C)(Nc2nc(N3CCOCC3)nc(Cl)c2CCO)C1
Temperature: 130 °C
Reaction time: 60 h
Yield: 129.3 %

Procedure:
To a solution of 2-[4,6-dichloro-2-(morpholin-4-yl)pyrimidin-5-yl]ethanol (Preparation 1) (7.8 g, 28.0 mmol) and tert-butyl(3S)-3-amino-3-methylpyrrolidine-1-carboxylate (Preparation 4) (8.4 g, 42.1 mmol) in NMP (58 mL) was added DIPEA (18.1 g, 140 mmol) at 15° C. and the resulting mixture was stirred at 130° C. for 60 h. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL). The aqueous layer was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL×5), dried over Na2SO4, filtered and concentrated to give 16 g of a brown gum. The crude product was purified by silica gel column chromatography eluting with a gradient of petroleum ether/EtOAc (20:1 to 8:1) to give the title compound (9.1 g, 73%) as a light yellow solid. m/z (APCI+) for C20H32N5O4Cl 442.0 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]#[CH:12])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[O:4][C@@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([NH:34][C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([NH:34][C@H:35]([C:37]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]#[CH:12])[C:6]3[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=3[O:4][C@@H:3]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:38])[CH3:36])=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: C#CCN1C(=O)[C@@H](N)[C@@H](c2ccccc2)Oc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C#CCN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)[C@@H](c2ccccc2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a stirred solution of (2R,3S)-3-amino-2-phenyl-5-prop-2-yn-1-yl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (67c) (65 mg, 0.222 mmol) in dichloromethane (3 mL) was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (1e) (65 mg, 0.267 mmol), HOBt (40 mg, 0.296 mmol), NMM (31 mg, 0.306 mmol) and EDAC-HCl (55 mg, 0.286 mmol). After stirring at ambient temperature under nitrogen overnight the solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic solution was separated, washed with 1N aqueous HCl then dried, filtered and evaporated. The residue was purified by recrystallization from 1:1 (v/v) ethyl acetate:hexanes to afford the title compound (86 mg, 74%) as a white solid. TLC Rf=0.25 (diethyl ether). 1H NMR (300 MHz, CDCl3) δ1.22 (d, 3H, J=7.0 Hz), 2.31 (m, 1H), 3.48 (s, 2H), 4.23 (m, 1H), 4.69 (d, 2H, J=2.2 Hz), 5.11 (t, 1H, J=7.0 Hz), 5.69 (d, 1H, J=7.4 Hz), 5.87 (d, 1H), 6.18 (d, 1H), 6.69-6.86 (m, 3H), 7.26-7.53 (m, 9H). MS APCI, m/z=518 (M+1). LC/MS: 2.63 min.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]([CH3:52])[CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH3:52])[CH:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C(=O)CCl)C1CCOCC1
Product: CCN(Cc1ccc(OCCN(C)C2CCOCC2)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 37.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N-(tetrahydropyran-4-yl)acetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.1 mg) was obtained.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH:13]1[CH2:23][CH2:22][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14]1>>[CH2:20]([O:19][C:17]([CH:16]1[CH2:22][CH2:23][N:13]([C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:14][CH2:15]1)=[O:18])[CH3:21]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCOC(=O)C1CCNCC1
Product: CCCCCCC/C=C/C(=O)N1CCC(C(=O)OCC)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and ethyl isonipecotate as starting raw materials, to produce an intended compound.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1C1C=CC=CC=1.Br[C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1.IC1C=CC=CC=1>>[N+:37]([C:36]1[C:31]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])=[N:32][CH:33]=[CH:34][CH:35]=1)([O-:39])=[O:38]
Reactant: O=[N+]([O-])c1cccnc1Br
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Agent: Cl
Solvent: Ic1ccccc1
Product: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ncccc3[N+](=O)[O-])c(=O)c2)cc1

Procedure:
4-[3-(3'-Nitro-2-oxo-2H-[1,2']bipyridinyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 2-bromo-3-nitropyridine for the iodobenzene in Step 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26]C)[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][OH:30])[C:10]=2[CH:9]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([OH:26])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][OH:30])[C:10]=2[CH:9]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCO)C(=O)NC3=O
Agent: BrB(Br)Br
Product: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1c2c2cc(O)ccc2n1CCO
Yield: 87 %

Procedure:
The reaction of 4-(2-Chlorophenyl)-6-(2-hydroxyethyl)-9-methoxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (V; Ar=2-chlorophenyl, R10═CH2CH2OH) (46) prepared according to example 43 with BBr3 using the procedure described in example 80 gave the 4-(2-Chlorophenyl)-6-(2-hydroxyethyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (VI; Ar=2-chlorophenyl, R10═CH2CH2OH) (47) in a yield of 87% as a yellow/orange powder; mp 265° C. (dec). 1H NMR δ (CD3)2SO] 11.04 (br s, 1H), 9.33 (br s, 1H), 8.38 (d, J=2.4 Hz, 1H), 7.75 (s, 1H), 7.60–7.56 (m, 2H), 7.52–7.43 (m, 4H), 7.12 (dd, J=8.8, 2.4 Hz, 1H), 4.83 (t, J=5.5 Hz, 1H), 4.49 (t, J=5.2 Hz, 2H), 3.77 (dt, J=5.5, 5.2 Hz, 2H), Found: C, 63.41; H, 4.11; N, 6.32. C22H15ClN2O4.1/2H2O requires C, 63.54; H, 3.87; N, 6.73.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][C:9]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)(=O)=O.[NH:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20]1>>[OH:18][C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:10][CH2:11][CH:6]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20]2)[CH2:7][CH2:8]1
Reactant: CS(=O)(=O)OC1CCC(O)(c2ccccn2)CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C2CCC(O)(c3ccccn3)CC2)C1
Reaction time: 0.25 h

Procedure:
The 4-hydroxy-4-pyridin-2-ylcyclohexyl methanesulfonate (0.245 g, 0.9 mmol) and tert-butyl (3R)-pyrrolidine-3-ylcarbamate (1.6 g, 8.59 mmol) were weighed into a microwave oven tube. The neat reaction mixture was placed into the microwave oven for 15 minutes at 71° C. The mixture was chromatographed on silica gel, eluting with 1% NH4OH in ethyl acetate/methanol (100/0 to 10/90), providing tert-butyl [(3R)-1-(4-hydroxy-4-pyridin-2-ylcyclohexyl)pyrrolidin-3-yl]carbamate. LC/MS: 362.2 (M+H, 100%). 1H NMR (CDCl3) δ 8.52 (m, 1H), 7.70 (m, 1H), 7.43 (d, 1H), 7.19 (m, 1H), 4.86 (bs, 2H), 4.20 (bs, 1H), 2.82 (m, 1H), 2.68 (s, 1H), 2.56 (m, 1H), 2.40 (m, 1H), 2.31 (s, 1H), 2.27-2.17 (m, 3H), 2.04-1.98 (m, 2H), 1.78-1.74 (m, 3H), 1.61 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.Cl.[CH3:14][CH2:15]O>>[CH2:14]([O:11][C:10]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([CH2:8][OH:9])[N:4]=1)=[O:12])[CH3:15]
Reactant: CCO
Reactant: O=C(O)c1nc(CO)ncc1Br
Agent: Cl
Product: CCOC(=O)c1nc(CO)ncc1Br
Yield: 80 %

Procedure:
A solution of 4.2 g (18.02 mmol) 5-bromo-2-hydroxymethyl-pyrimidine-4-carboxylic acid in 50 ml 5N HCl/EtOH was stirred for 5 hrs. at RT. After evaporation of the solvent the residue was distributed between 50 ml CH2Cl2 and 30 ml H2O. The organic phase was washed with sat. NaHCO3 and brine. The combined organic phases were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography to give 3.80 g (80%) 5-bromo-2-hydroxymethyl-pyrimidine-4-carboxylic acid ethyl ester as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][CH:9]=2)=[CH:6][CH:5]([O:20][CH3:21])[O:4]1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][O:2][CH:3]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[CH:16][CH:17]=[CH:18][N:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH:5]([O:20][CH3:21])[O:4]1
Reactant: COC1C=C(c2ccc(-c3ncccn3)cc2)C(OC)O1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC1CC(c2ccc(-c3ncccn3)cc2)C(OC)O1
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A mixture of 2,5-dihydro-2,5-dimethoxy-3-[4-(pyrimidin-2-yl)phenyl]furan (70 mg, 0.25 mmol), 10% Pd/C (20 mg), and ammonium formate (46 mg, 0.75 mmol) in methanol (1 mL) was stirred overnight. The reaction mixture was filtered through a fritted funnel, and concentrated in vacuo. The crude product was partitioned between ethyl acetate and sat. aq. NaHCO3, the organic layer dried with Na2SO4, and concentrated in vacuo to give 60 mg (85%) of the title compound, which was used without further purification. MS 287 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][OH:20])[CH:13]=1)[CH2:8][CH2:9][F:10])([CH3:4])([CH3:3])[CH3:2]>CC#N.O=[Mn]=O>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=[O:20])[CH:13]=1)[CH2:8][CH2:9][F:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCF)Cc1ccc(Cl)c(CO)c1
Agent: O=[Mn]=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CCF)Cc1ccc(Cl)c(C=O)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100.5 %

Procedure:
MnO2 (1.22 g, 12.6 mmol) was added to a sol. of (4-chloro-3-hydroxymethyl-benzyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester (801 mg, 2.52 mmol) in CH3CN (50 mL). The mixture was stirred at rt for 4.5 h, and MnO2 (1.22 g, 12.6 mmol) was added again. The mixture was stirred for 1 h, and was filtered over Celite. The precipitate was washed with CH3CN and CH2Cl2. The filtrate was evaporated under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (800 mg, quantitative yield) that was used further without purification. LC-MS: tR=1.01 min.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:8][CH:7]=[C:6]([F:15])[C:3]=1[CH:4]=[O:5].ClC1C(OCC(F)(F)F)=CC=C(Cl)C=1C(C1C2C(=NC=C(C3C=NN(C)C=3)C=2)NC=1)O.[Cl:47][C:48]1[CH:49]=[C:50]2[CH:56]=[CH:55][NH:54][C:51]2=[N:52][CH:53]=1>>[Cl:1][C:2]1[C:9]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:8][CH:7]=[C:6]([F:15])[C:3]=1[C:4]([C:56]1[C:50]2[C:51](=[N:52][CH:53]=[C:48]([Cl:47])[CH:49]=2)[NH:54][CH:55]=1)=[O:5]
Reactant: Clc1cnc2[nH]ccc2c1
Reactant: COCCOc1ccc(F)c(C=O)c1Cl
Agent: Cn1cc(-c2cnc3[nH]cc(C(O)c4c(Cl)ccc(OCC(F)(F)F)c4Cl)c3c2)cn1
Product: COCCOc1ccc(F)c(C(=O)c2c[nH]c3ncc(Cl)cc23)c1Cl

Procedure:
Additional compounds were prepared using the protocol of Scheme 41, optionally substituting 2-chloro-6-fluoro-3-(2-methoxy-ethoxy)-benzaldehyde 123 with a suitable aldehyde (prepared as described in Examples 36, 39 or 40), and/or optionally replacing 5-chloro-1H-pyrrolo[2,3-b]pyridine 4 with an appropriate substituted 7-azaindole (5-methoxy-7-azaindole per Example 8, 5-(1-methyl-1H-pyrazol-4-yl)-7-azaindole per Example 35) in Step 1. The following compounds were made following this procedure:
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[C:15]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[CH2:4][CH2:3]1.[BH4-].[Na+]>CO.O>[NH:2]1[CH2:3][CH2:4][CH:5]([CH:8]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]2=3)[CH2:6][CH2:7]1
Reactant: CN1CCC(C(=O)c2ncccc2CCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: c1ccc2c(c1)CCc1cccnc1C2C1CCNCC1
Yield: 97.6 %

Procedure:
To a mixture of 5.0 g (16.2 mmole) of (1-methyl-4-piperidinyl) [3-(2-phenylethyl)-2-pyridinyl]methanone (which can be prepared in the same manner as described in Preparative Example 1, Steps A-D) in 70 mL of methanol was added portionwise 0.8 g (21.1 mmole) of sodium borohydride. The next day the solution was concentrated in vacuo to give a slurry which was dissolved in water and extracted with CHCl3. The combined organic portions were dried over MgSO4, filtered, and concentrated in vacuo to provide a liquid which was distilled (bp 190°-195° C. 1 mm Hg) to give 4.4 gms of the title compound as a viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(Cl)CCl.CCN(C(C)C)C(C)C>O1CCCC1.ClCCl.O>[N:21]1([C:18]([C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[S:10][C:11]=3[CH:17]=2)=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(C(=O)O)cc2s1
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc2ccc(C(=O)N3CCCC3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
In a 250 ml flask was added 2-(tert-butoxycarbonyl-amino)benzo[d]thiazole-6-carboxylic acid (1.0 g, 3.4 mmol) and pyrrolidine (0.559 mL, 6.8 mmol) in tetrahydrofuran (50 mL). To this solution was added EDC (1.3 g, 6.8 mmol), 1-hydroxybenzotriaxole (1.041 g, 6.8 mmol) and Hunig's Base (2.37 mL, 13.59 mmol). The reaction was stirred at 25° C. for 1 hour. The reaction was then poured into water and dichloromethane. The water was extracted 3 times with dichloromethane and the organic layers were combined and concentrated. The residue was taken up in a small amount of dichloromethane and precipitated out with diethyl ether/hexanes. The flask was put in the freezer for 1 hour and filtered. The white precipitate was collected to yield tert-butyl 6-(pyrrolidine-1-carbonyl)benzo[d]thiazol-2-ylcarbamate (1.09 g, 3.14 mmol, 92% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.95 (s, 1H), 8.14 (s, 1H), 7.61-7.77 (m, J=8.39, 1.98 Hz, 1H), 7.46-7.63 (m, 1H), 3.39-3.63 (m, 4H), 1.74-2.00 (m, 4H), 1.45-1.62 (m, 9H). MS (LC/MS) R.T.=3.40; [M+H]+=363.1.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]([NH:20][C:21]2[CH:33]=[CH:32][C:24]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:23][CH:22]=2)=[O:19])[C:8]1=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].FC(F)(F)C(O)=O>>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]([NH:20][C:21]2[CH:33]=[CH:32][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)=[O:19])[C:8]1=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1c(=O)c(C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCn1c(=O)c(C(=O)Nc2ccc(C(=O)O)cc2)c(O)c2ccccc21
Temperature: 0 °C

Procedure:
tert-Butyl 4-(1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)benzoate (83 mg, 0.18 mmol) is added, in fractions, to a solution of trifluoroacetic acid (TFA) cooled to 0° C.; the mixture is left to react for 3 hours. The crude product obtained is washed with ethyl ether until a white crystalline solid forms. The product is dried to give a yield of 61 mg (83%). 1H NMR (DMSO): δ 8.16 (d, J=8 Hz, 1H), 7.97-7.65 (m, 6H), 7.38 (m, 1H), 4.27 (bs, 2H), 1.59 (bs, 2H), 1.39 (bs, 2H), 1.28 (bs, 5H), 0.84 (bs, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:5].[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:4]([C:3]1[C:6]([OH:10])=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:21])#[N:5]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: N#Cc1c(N)cccc1O
Product: N#Cc1c(O)cccc1NC(=O)NC(=O)c1ccccc1

Procedure:
Prepared as in Example 53a from 2-amino-6-hydroxybenzonitrile and benzoyl isocyanate as an off-white solid (166 mg, 46%). 1H NMR (400 MHz, DMSO-d6) δ6.76 (d, J=8.4 Hz, 1H), 7.46 (t, J=8 Hz, 1H), 7.54 (t, J=8 Hz, 2H), 7.66-7.73 (m, 2H), 8.04-8.06 (d, J=8 Hz, 2H), 11.24 (s, 1H), 11.30 (s, 1H), 11.42 (s, 1H). MS 281 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH2:18])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:20]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH:18][C:27]([CH:20]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:28])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1
Reactant: O=C(Cl)C1CCCCCC1
Solvent: c1ccncc1
Product: O=C(Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1)C1CCCCCC1
Yield: 29.7 %

Procedure:
A solution of amine 8 (0.200 g, 0.78 mmol) in dry Pyridine (5 ml) and cycloheptane carbonyl chloride (0.200 ml, 1.24 mmol) was heated at 80° C. for 2 h. The reaction was quenched by addition of water and the yellow product was filtered, air dried and passed through a SiO2 gel column. Eluting with hexane: EtOAc (6:4) yielded the desired product 18 (0.088 g, 30%); 1H NMR (DMSO-d6, 500 MHz): δ10.38 (1H, brs, NH), 8.76 (1H, brs, NH), 8.44-8.39 (4H, m), 8.33 (1H, brs), 2.92 (1H, m), 1.86-145 (12H, m), EIMS m/z: 380 (M+1), 739.1 (M+).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[N:5]1)([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:22]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.[Cl-].[Na+].O>[Cl:22][C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][C:7]=1[N+:9]([O-:11])=[O:10]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)n1cc([N+](=O)[O-])cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1ncc([N+](=O)[O-])c1Cl
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 84 %

Procedure:
To a solution of 1-isopropyl-4-nitro-1H-pyrazole (1 equiv) in THF (0.65 M) was added dropwise a 1.0 M solution of lithium bis(trimethylsilyl)amide (2.6 equiv) in THF at −78° C. The reaction was stirred at −78° C. for 30 min before the addition of hexachloroethane (1.5 equiv) in THF (1.63 M). The reaction was stirred at −78° C. for 2.5 h then warmed to room temperature. The reaction was diluted with brine and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (10-20% ethyl acetate in petroleum ether) to afford the desired product (84% yield) as a white solid. MS (ESI) m/z 190.1 [M+H]+.
Reaction SMILES: [Br-:1].[Li+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4]1>C(#N)C.O>[Br:1][C:10]1[CH:9]=[CH:8][C:7]2[O:3][CH2:4][O:5][C:6]=2[CH:11]=1
Reactant: [Br-]
Reactant: c1ccc2c(c1)OCO2
Agent: [Li+]
Solvent: O
Solvent: CC#N
Product: Brc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ceric ammonium nitrate (9.88 g, 18.0 mmol) and lithium bromide (1.5 g, 18.0 mmol) in acetonitrile (20 mL) was stirred for 30 minutes at 25° C. under nitrogen atmosphere. A solution of benzo[1,3]dioxol (2 g, 16 mmol) in acetonitrile (20 mL) was added slowly to it and the mixture was stirred for 4 hours at 25° C. The mixture was then diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were collected, combined, washed with water (50 mL), dried over anhydrous sodium sulphate, and concentrated under vacuum to give the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: COC(=O)c1ccc(O)c(C(=O)O)c1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(O)c(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.8 %

Procedure:
To a solution of 2-hydroxy-5-(methoxycarbonyl)benzoic acid (4.0 g, 20.4 mmol) in DMF (40 mL) was added KHCO3 (2.04 g, 20.4 mmol) and benzyl bromide (3.49 g, 20.4 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirring was continued for 20 h. The reaction mixture was diluted with water, extracted with EtOAc (2×) and the combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a crude oil. The crude material was purified by flash chromatography (gradient from 0% to 30% EtOAc/hexanes) to provide the title compound (5.3 g, 92%) as an off-white solid. 1H NMR (CDCl3) δ 11.21 (s, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.11 (dd, J=8.8, 2.4 Hz, 1H), 7.47-7.37 (m, 5H), 7.01 (d, J=8.8 Hz, 1H), 5.42 (s, 2H), 3.89 (s, 3H); MS(ESI−) m/z 285.2 (M−H)−.
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[CH:8]=[N:9][CH:10]=[CH:11][C:2]1=2.[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([Br:26])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19]>O>[Br:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([Br:26])[C:23]=1[O:24][CH3:25])[C:18]([N:4]1[C:5](=[O:7])[CH2:6][O:1][C:2]2[CH:11]=[CH:10][N:9]=[CH:8][C:3]1=2)=[O:19]
Reactant: O=C1COc2ccncc2N1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1c(Br)cc(C(=O)N2C(=O)COc3ccncc32)cc1Br

Procedure:
By the same method as in Example 56, 4H-pyrido[4,3-b][1,4]oxazin-3-one (200 mg, 1.33 mmol), sodium hydride (56 mg, 1.40 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (437 mg, 1.33 mmol) were reacted, and then water was added thereto and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of ethyl acetate:methanol=9:1. The fractions containing the product were collected and evaporated to obtain the target compound 57, i.e., 4-(3,5-dibromo-4-methoxy-benzoyl)-4H-pyrido[4,3-b][1,4]oxazin-3-one, as white solid (125 mg, 21%).