Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:21]([OH:23])=[O:22])=[C:7]2[C:11]=1[O:10][C:9]([CH:12]([O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:13])=[CH:8]2.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:22][C:21]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:11]3[O:10][C:9]([CH:12]([O:14][CH:15]4[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)[CH3:13])=[CH:8][C:7]=23)=[O:23])=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(C(=O)O)c2cc(C(C)OC3CCNCC3)oc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(C(C)OC3CCNCC3)oc12
Yield: 27.5 %

Procedure:
Prepared from 7-methoxy-2-(1-methyl-piperidin-4-yloxymethyl)-benzofuran-4-carboxylic acid (1.9 g), 4-nitrophenol (835 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.15 g) and 4-dimethylaminopyridine (catalytic amount) in dichloromethane (40 ml). Purification by column chromatography eluting with 10% methanol in dichloromethane afforded the desired product as a pale yellow solid (720 mg).
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([CH:31]([CH3:33])[CH3:32])[C:23]=2[CH:22]=[C:21](/[C:34](/[CH3:39])=[C:35](/[F:38])\[CH:36]=O)[C:20]=1[O:40][CH2:41][CH3:42]>>[Br:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([CH:31]([CH3:33])[CH3:32])[C:23]=2[CH:22]=[C:21](/[C:34](/[CH3:39])=[C:35](/[F:38])\[CH:36]=[CH:9]\[C:10](\[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:20]=1[O:40][CH2:41][CH3:42]
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Reactant: CCOc1c(/C(C)=C(/F)C=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(c(Br)c1OCC)C(C)(C)CC=C2C(C)C

Procedure:
Following General Procedure I-1, ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2E-enoate (1.3 g, 4.95 nmol) and (2E)-3-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-enal (Compound A-147, 675 mg, 1.65 mmol) were reacted to give the title compound as a colorless oil after purification by column chromatography (silica gel, 2% ethyl acetate in hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28]([O:30]C)=O)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH2:36]([NH2:38])[CH3:37]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28]([NH:38][CH2:36][CH3:37])=[O:30])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Reactant: CCN
Product: CCNC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Yield: 76 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.53 mmol) was reacted with ethylamine to give the title compound as a white solid (195 mg, 76%); NMR Spectrum 1.04 (t, 3H), 1.65 (d, 3H), 3.14-3.20 (m, 2H), 5.16 (q, 1H), 5.71 (s, 2H), 7.01 (d, 1H), 7.04-7.12 (m, 3H), 7.36 (dd, 2H), 7.72-7.78 (m, 3H), 8.17 (s, 1H), 8.44 (m, 1H), 8.53 (s, 1H), 8.56 (s, 1H), 10.68 (br s, 1H); Mass spectrum MH+ 485.
Reaction SMILES: C(OC(Cl)=O)C.[C:7]([C:10]12[CH2:17][CH2:16][C:13]([C:18]#[N:19])([CH2:14][CH2:15]1)[CH2:12][CH2:11]2)(O)=[O:8].C([N:22](CC)CC)C.N>C(Cl)(Cl)Cl>[NH2:22][C:7]([C:10]12[CH2:17][CH2:16][C:13]([C:18]#[N:19])([CH2:14][CH2:15]1)[CH2:12][CH2:11]2)=[O:8]
Reactant: CCN(CC)CC
Reactant: N#CC12CCC(C(=O)O)(CC1)CC2
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: N#CC12CCC(C(N)=O)(CC1)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
2.6 ml of ethylchloroformate are rapidly added, dropwise, to a solution of 4.9 g of 1-carboxy-4-cyano-bicyclo[2.2.2]-octane and 3.8 ml of triethylamine in 130 ml of chloroform at -10° C. After 15 minutes of stirring, ammonia gas is introduced to the mixture for 10 minutes. The mixture is stirred for 10 minutes at 0° C., warmed to ambient temperature and after an hour, evaporated to dryness. The residue is stirred with water under heating, cooled, suction filtered, washed with water and dried. The 1-aminocarbonyl-4-cyano-bicyclo[2.2.2]octane [4.2 g (86% of theory); Rf value: 0.78 (Silica gel; methylene chloride/methanol/conc. aqueous ammonia=4:1:0.2)] obtained is suspended in 100 ml of acetonitrile/water (1:1), combined with 15.0 g of bis(trifluoroacetoxy)iodobenzene and stirred for 18 hours at ambient temperature. The reaction mixture is evaporated down to half its volume, shaken twice with ehtyl acetate and the aqueous phase is adjusted to a pH of 12 to 13. The aqueous phase is extracted 3 times with ethyl acetate and the combined organic phases are washed with saturated saline solution and dried. The residue is dissolved in ethyl acetate acid and a little acetone and ethereal hydrochloric acid are added. The mixture is cooled in an ice-bath, suction filtered and the product is washed with ethyl acetate.
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].C[O:6][C:7](=O)[CH2:8][CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[C:14]([C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[N:13][N:12]=1>CO.O.[OH-].[Na+]>[OH:4][NH:3][C:7](=[O:6])[CH2:8][CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[C:14]([C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[N:13][N:12]=1
Reactant: COC(=O)CCCc1nnc(-c2nccs2)c2cc(OC)ccc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1ccc2c(CCCC(=O)NO)nnc(-c3nccs3)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.4 %

Procedure:
A solution of sodium (388 mg, 16.9 mmoles) in CH3OH (6 ml) was added with hydroxylamine hydrochloride (1.3 g, 18.71 mmoles). The resultant solution was added to a solution of 4-(6-methoxy-4-thiazol-2-yl-phthalazin-1-yl)-butyric acid methyl ester (1.5 g, 4.4 mmoles), prepared as described in example 115, in CH3OH (30 ml), and stirred at room temperature for 2 days, then refluxed for 7 hours. NH2OH.HCl (1.6 g) and sodium (450 mg) were added, and the mixture was refluxed. After 1 night further NH2OH.HCl (0.9 g) and sodium (257 mg) were added, and the mixture was refluxed for 24 hours. The precipitate was filtered off and the mother liquors dried, taken up in water and filtered. The resultant solid was chromatographed (eluent: CH2Cl2/CH3OH 95:5) to give a solid which was suspended in water, dissolved in 10% NaOH and precipitated with saturated ammonium chloride to give 430 mg of the title compound (yield: 28.6%). m.p.: 189-190° C. (dec.).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:55])([CH3:54])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:53])([C@@:17]4([CH3:52])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([NH:38][CH2:39][CH2:40][N:41]([CH2:47][C:48]([O:50]C)=[O:49])[CH2:42][C:43]([O:45]C)=[O:44])=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>O1CCOCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([CH3:55])([CH3:54])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:53])([C@@:17]4([CH3:52])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([NH:38][CH2:39][CH2:40][N:41]([CH2:47][C:48]([OH:50])=[O:49])[CH2:42][C:43]([OH:45])=[O:44])=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC(=O)OC)CC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC(=O)O)CC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 78 °C

Procedure:
A mixture of dimethyl 2,2′-(2-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxamido)ethylazanediyl)diacetate (17 mg, 0.022 mmol) and 1 N sodium hydroxide (0.112 mL, 0.112 mmol) in dioxane (0.5 mL) was heated up at 78° C. for 3 hours. LCMS indicated the formation of desired product. The reaction mixture was filtered and the clear solution was purified by prep HPLC to provide the title compound (10 mg, 59%) as white solid. LCMS: m/e 717.35 (M+H)+, 1.97 min (method 1). 1H NMR (500 MHz, Acetic Acid-d4) δ ppm 8.03 (d, J=7.93 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.88 Hz, 1H), 4.78 (s, 1H), 4.64 (s, 1H), 4.35-4.14 (m, 4H), 3.94-3.81 (m, 1H), 3.71-3.61 (m, 1H), 3.60-3.49 (m, 2H), 3.18-3.06 (m, 1H), 2.53 (td, J=12.13, 3.51 Hz, 1H), 2.24-2.13 (m, 2H), 1.75 (s, 3H), 2.10-1.09 (m, 19H), 1.08 (s, 3H), 1.06 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: BrCCc1ccccc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(CCc2ccccc2)c1
Temperature: 80 °C

Procedure:
To a solution of 4-nitro-1H-pyrazole (1.50 g, 12.87 mmol) in MeCN (30 mL), (2-bromoethyl)benzene (1.97 mL, 14.15 mmol) and Cs2CO3 (4.61 g, 14.15 mmol) was added. The resulting mixture was refluxed (80° C.) for 1.5 h, then the reaction mixture was allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM and the filtrate was concentrated in vacuo to obtain 4-nitro-1-phenethyl-1H-pyrazole as a beige solid which was used in the next step without further purification. LC-MS conditions A: tR=0.92 min; [M+H]+=217.97.
Reaction SMILES: [CH:1]([N:4]([CH:15]([CH3:17])[CH3:16])[CH2:5][CH2:6][NH:7][C:8](N1C=CN=C1)=[O:9])([CH3:3])[CH3:2].[NH2:18][CH2:19][C:20]1[N:28]=[C:27]2[C:23]([N:24]=[CH:25][N:26]2[C@H:29]2[C@H:33]([OH:34])[C@H:32]([OH:35])[C@@H:31]([CH2:36][OH:37])[O:30]2)=[C:22]([NH:38][CH2:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:21]=1.C1(C)C=CC=CC=1.C(O)(C)C>ClCCl>[OH:34][C@@H:33]1[C@H:32]([OH:35])[C@@H:31]([CH2:36][OH:37])[O:30][C@H:29]1[N:26]1[CH:25]=[N:24][C:23]2[C:27]1=[N:28][C:20]([CH2:19][NH:18][C:8]([NH:7][CH2:6][CH2:5][N:4]([CH:15]([CH3:17])[CH3:16])[CH:1]([CH3:2])[CH3:3])=[O:9])=[N:21][C:22]=2[NH:38][CH2:39][CH:40]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Solvent: ClCCl
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(C)N(CCNC(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)C(C)C
Temperature: 25 °C
Yield: 26.5 %

Procedure:
N-[2-(Diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (84 mg, 0.35mmol) (Preparation 27) was added to a stirred solution of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydro-3,4-furandiol (150 mg, 0.35mmol) (Preparation 2) in dichloromethane (5 ml) at room temperature. The reaction was heated under reflux for 1 hour and then toluene (5 ml) and isopropanol (2 ml) were added. The dichloromethane was boiled off and the reaction was then heated under reflux for 1 hour. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 by volume increasing to 80:20:2 by volume). This gave the title compound as a foam (60 mg).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([Br:25])[C:17]=2[CH3:26])=[O:15])=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].Cl>CO>[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([Br:25])[C:17]=2[CH3:26])=[O:15])=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(Br)c3ccccn23)ccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(Br)c2ccccn2c1C(=O)c1ccc(N)c(C(=O)O)c1
Yield: 88.6 %

Procedure:
4.92 ml (4.92 mmol) of a 1N aqueous solution of sodium hydroxide are added, at ambient temperature, to 1.91 g (4.69 mmol) of methyl 2-amino-5-[(1-bromo-2-methylindolizin-3-yl)carbonyl]benzoate in 30 ml of methanol. The reaction medium is refluxed for 10 hours and then hydrolysed with a 1N aqueous solution of hydrochloric acid. The aqueous phase is extracted with ethyl acetate. The organic phase obtained is washed with water, dried over sodium sulphate, filtered, and concentrated under reduced pressure. The solid obtained is rinsed with diisopropyl ether and dichloromethane, and dried under reduced pressure overnight at 50° C. 1.55 g of a yellow solid are obtained.
Reaction SMILES: [OH:1][C:2]([CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])([CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:9])[C:3](O)=[O:4].Cl.C([O:35][NH2:36])(C)(C)C.CN1CCOCC1>C(Cl)Cl>[OH:35][NH:36][C:3](=[O:4])[C:2]([OH:1])([CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:9]
Reactant: CC(C)(C)ON
Reactant: COc1ccc(C(=O)NCC(O)(CS(=O)(=O)c2ccc(OC)cc2)C(=O)O)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(C(=O)NCC(O)(CS(=O)(=O)c2ccc(OC)cc2)C(=O)NO)cc1
Reaction time: 6 h
Yield: 67.5 %

Procedure:
2-Hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(N-(4-methoxybenzenecarbonyl)amino)-propionic acid (100 mg, 0.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiilnide hydrochloride (68 mg, 0.35 mmol), O-tert-butylhydroxylamine hydrochloride (118 mg, 0.944 mmol), and 4-methylmorpholine (131 mg, 0.354 mmol) are dissolved in 20 mL of methylene chloride. The reaction mixture is stirred under nitrogen for 6 hours. The solvent is removed under reduced pressure, and the residue is dissolved in ethyl acetate. The organic layer is washed with 1N sodium hydrogen sulfate, 5% sodium bicarbonate, and saturated brine and dried over magnesium sulfate. The solvent is removed to yield 71 mg of white solid which is recrystallized from methanol. The tert-butyl protecting group is removed by treatment with 50% trifluoroacetic acid in methylene chloride for 24 hours. The solvents are removed, and the crude product is purified by reverse phase chromatography on a C18 Vydac column using a water-acetonitrile elution system to yield the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:22]C(=O)OC(C)(C)C)[C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:30].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH2:22])[C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)c1nccs1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of tert-butyl (S)-[2-(4-benzyloxyphenyl)-1-(thiazol-2-yl)ethyl]carbamate (112 mg, 0.273 mmol) in ethyl acetate (1 ml) was added 4N HCl-ethyl acetate solution (1 ml), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, and hexane:diethyl ether (3:1) solution was added to the obtained residue. The precipitated solid was collected by filtration and washed with hexane:diethyl ether (3:1) solution. The obtained solid was dried in vacuo to give (S)-2-(4-benzyloxyphenyl)-1-(thiazol-2-yl)ethylamine hydrochloride (66 mg, yield 70%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22](=[O:23])[C:21]3[C:20]([C:24]([OH:26])=O)=[CH:19][CH:18]=[CH:17][C:16]=3[CH:15]2[CH3:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:29](C)C=O.C(N(CC)C(C)C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:24](=[O:26])[NH2:29])[CH:15]2[CH3:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC1c2cccc(C(=O)O)c2C(=O)N1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1c2cccc(C(N)=O)c2C(=O)N1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To an orange solution of 2-(1-tert-butoxycarbonyl-piperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (3.8 g, 10.3 mmol) in N,N-dimethylformamide (60 mL) hydroxybenzotriazole ammonium salt (3.15 g, 20.7 mmol), 1-ethyl-3-(3′-dimethylamino) carbodiimide hydrochloric acid salt (3.34 g, 20.7 mmol) and N,N-diisopropylethylamine (5.3 mL, 30.9 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduce pressure and the residue was dissolved in ethyl acetate. The solution was washed twice with sodium carbonate saturated aqueous solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude was purified by flash chromatography (dichloromethane/methanol: 97:3) to afford the title compound (2.86 g, 74%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C@@H:5]([CH:13]([CH3:15])[CH3:14])[N:6]=[C:7]([O:10][CH2:11][CH3:12])[CH2:8][N:9]=1)[CH3:2].[Li]CCCC.CCCCCC.Br[CH2:28][C@@H:29]([CH:45]([CH3:47])[CH3:46])[CH2:30][C:31]1[CH:39]=[C:38]2[C:34]([CH:35]=[N:36][N:37]2[CH2:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:33][CH:32]=1>C1COCC1>[CH2:11]([O:10][C:7]1[C@H:8]([CH2:28][C@@H:29]([CH:45]([CH3:47])[CH3:46])[CH2:30][C:31]2[CH:39]=[C:38]3[C:34]([CH:35]=[N:36][N:37]3[CH2:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:33][CH:32]=2)[N:9]=[C:4]([O:3][CH2:1][CH3:2])[C@@H:5]([CH:13]([CH3:15])[CH3:14])[N:6]=1)[CH3:12]
Reactant: CCOC1=N[C@H](C(C)C)C(OCC)=NC1
Reactant: COCCCn1ncc2ccc(C[C@@H](CBr)C(C)C)cc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC1=N[C@H](C(C)C)C(OCC)=N[C@H]1C[C@H](Cc1ccc2cnn(CCCOC)c2c1)C(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a stirred solution of (R)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine (480 mg, 2.3 mmol) in anhydrous THF (7 mL) at −78° C. was added dropwise 2.5 M n-BuLi in hexane (0.9 mL, 2.3 mmol). After stirring for 2 h at −78° C., a solution of (R)-6-(2-(bromomethyl)-3-methylbutyl)-1-(3-methoxypropyl)-1H-indazole (530 mg, 1.5 mmol) in THF (2 mL) was added dropwise. The mixture was stirred for 1 h at −78° C., then warmed to rt and stirred for 12 h. The reaction mixture was quenched with satd aq NH4Cl and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, evaporated, and purified by flash chromatography on silica gel to give 6-((S)-2-(((2S,5R)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazin-2-yl)methyl)-3-methylbutyl)-1-(3-methoxypropyl)-1H-indazole (493 mg, 68%). MS: 485 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:11][C:12]([NH:14]C(=O)OCC)=S)=[N:5][C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.Cl.NO.C([N:26](C(C)C)CC)(C)C>C(O)C>[NH2:26][C:12]1[N:11]=[C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[C:6]([O:9][CH3:10])[N:5]2[N:14]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1nc(OC)ccc1OC
Agent: Cl
Agent: NO
Solvent: CCO
Product: COc1ccc(OC)n2nc(N)nc12
Reaction time: 0.25 h
Yield: 61.8 %

Procedure:
A mixture of 58.4 g (0.21 mole) of ethyl [(3,6-dimethoxypyridin-2-yl)amino]carbonothioylcarbamate, 70 g (1 mole) of hydroxylamine hydrochloride and 105 mL (0.6 mole) of diisopropylethylamine in 1 liter of ethanol was heated to reflux for 12 hr. After cooling, the resulting solution was evaporated to dryness under vacuum. Water (250 ml) and diethyl ether (100 ml) were added to the residue and the mixture was stirred for 15 min. The product was collected by filtration and dried under a vacuum at room temperature to give 25.2 g of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-a]pyridine.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:19](=[O:21])[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:17])[CH:11]=2)[C:8]=1[CH3:9])(=[O:3])[CH3:2].Br[CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([C:4]1[C:5]([C:19](=[O:21])[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:23][CH3:24])=[C:12]([CH3:17])[CH:11]=2)[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CCBr
Reactant: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)c(C)c2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)cc1C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[4-acetyl-1-(4-hydroxy-3-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (prepared as in Example 61) (90 mg, 0.32 mmol) in 3 mL of dry DMF was added bromoethane (108 mg, 1.0 mmol) and K2CO3 powder (50 mg). The resulting reaction mixture was warmed to 50° C. and stirred for 1 h. It was quenched by addition of 20 mL of H2O, extracted with diethyl ether (20 mL×2). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford 1-[4-acetyl-1-(4-ethoxy-3-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 314 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:22]([C:19]1[CH:18]=[N:17][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([N:30]5[CH2:29][CH2:28][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31]5)[CH:26]=[CH:25][C:5]=4[N:6]=3)[CH2:11][CH2:12]2)=[N:21][CH:20]=1)[CH2:23][CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
To a degassed solution of 6-bromo-2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazole (360 mg, 0.831 mmol), tert-butyl piperazine-1-carboxylate (387 mg, 2.077 mmol), sodium tert-butoxide (319 mg, 3.32 mmol) and BINAP (10.4 mg, 0.017 mmol) in toluene (5.5 mL) was added Pd2(dba)3 (45.6 mg, 0.050 mmol). Upon completion of addition, the reaction mixture was stirred in a sealed vial at 80° C. overnight. At the conclusion of this period, the reaction mixture was cooled to rt, diluted with water and then extracted with EtOAc (3×5 mL). The combined organic layers were washed with saturated NaHCO3 (5 mL) and brine (5 mL), dried (Na2SO4), filtered, and then concentrated to yield the crude product. The crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 60% EtOAc) to afford Compound 12A as a white solid (248 mg, 0.460 mmol, 55% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 8.18 (2H, s), 7.54-7.61 (1H, m), 7.15-7.23 (1H, m), 6.99-7.07 (1H, m), 5.37-5.44 (1H, m), 4.17-4.27 (2H, m), 3.65-3.77 (2H, m), 3.55-3.65 (4H, m), 3.06-3.18 (4H, m), 2.42 (2H, t, J=7.6 Hz), 2.13-2.22 (2H, m), 1.89-2.00 (2H, m), 1.56-1.64 (2H, m), 1.50 (9H, s), 0.95 (3H, t, J=7.3 Hz). LC/MS (m/z)=539 (M+H)+.