Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:12]([C:15]1[CH:16]=[C:17]([C:24]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:27])=[O:25])[CH:18]=[C:19]([N+:21]([O-])=O)[CH:20]=1)([O-])=O.C>O1CCOCC1>[C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[NH2:12][C:15]1[CH:16]=[C:17]([C:24]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:27])=[O:25])[CH:18]=[C:19]([NH2:21])[CH:20]=1
Reactant: O=C(C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Agent: C
Agent: O=C(O)C=Cc1ccccc1
Solvent: C1COCCO1
Product: Nc1cc(N)cc(C(=O)C(=O)c2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
65.6 g (200 milimole) of 3,5-dinitrobenzil cinnamate, 10 g carbon black contained 5% Pt (product with water content of about 50%), and 500 ml of 1,4-dioxane were placed in a reaction vessel (hydrogenating apparatus). Then the reaction mixture were heated at 60° C. with stirring under a hydrogen atmosphere. In approximately two hours, 29 L of hydrogen was absorbed and the reaction was completed when the absorption of hydrogen stopped, and the filtrate was concentrated. The carbon black contained Pt was isolated by filtration. Thus, 53.6 g of 3,5-diaminobenzil cinnamate was yielded. The exothermic peak temperature was 230° C.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[I:6][C:7]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:9]([CH:10]=O)[C:8]=1[OH:19].C(N(CC)CC)C>C(Cl)Cl>[O:3]=[S:1]1(=[O:4])[N:2]=[CH:10][C:9]2[CH:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=[C:7]([I:6])[C:8]=2[O:19]1
Reactant: CC(C)(C)c1cc(I)c(O)c(C=O)c1
Reactant: NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1cc(I)c2c(c1)C=NS(=O)(=O)O2
Temperature: 20 °C
Yield: 13.7 %

Procedure:
To a solution of sulfamoyl chloride (13.8 g, 0.12 mole) in anhydrous methylene chloride (75 ml) is added a solution of 3-iodo-5-(1,1-dimethylethyl)salicylaldehyde (6 g., 0.02 mole) and triethylamine (12.1 g, 0.12 mole) in anhydrous methylene chloride (100 ml.) dropwise with stirring at 20° C. Upon completing the addition, the resulting reaction mixture is stirred at 20° C. for 3 days. Removal of the solvent in vacuo leaves a tacky residue which is partitioned between ether and 2 N hydrochloric acid. After separating the phases, the organic phase is washed with water and saturated brime, dried over sodium sulfate and filtered. Evaporation of the filtrate leaves an oily residue (6 g.) which is chromatographed on silica gel (300 g.) with benzene. Elution with benzene (840 ml.) gives recovered 3-iodo-5-(1,1-dimethylethyl)salicylaldehyde (2.2 g., 37% recovery), m.p. 76°-78° C. Continued elution with benzene (500 ml.) provides an impure solid (2.4 g.) which is triturated with hexane (20 ml.) and filtered to afford the title compound as a pale yellow solid (1.0 g, 14%), m.p. 130°-134° C. Crystallization from hexane benzene (9.1; viv) gives an analytical sample of 2,2-dioxo-6-(1,1-dimethylethyl)-8-iodo-1,2,3-benzoxathiazine, m.p. 135°-136° C.
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].C(OCOC)(=O)C.[C:13]([O:16][C@:17]1([C@:41]2([CH3:42])[C@H:27]([C@H:28]3[C@H:38]([CH2:39][CH2:40]2)[C@:36]2([CH3:37])[C:31](=[CH:32][C:33](=[O:43])[CH2:34][CH2:35]2)[CH2:30][CH2:29]3)[CH2:26][CH2:25]1)[C:18](=[O:24])[CH2:19][O:20][C:21](=[O:23])[CH3:22])(=[O:15])[CH3:14]>C(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)=O>[C:13]([O:16][C@:17]1([C@:41]2([CH3:42])[C@H:27]([C@H:28]3[C@H:38]([CH2:39][CH2:40]2)[C@:36]2([CH3:37])[C:31](=[CH:32][C:33](=[O:43])[CH2:34][CH2:35]2)[C:30]([CH3:1])=[CH:29]3)[CH2:26][CH2:25]1)[C:18](=[O:24])[CH2:19][O:20][C:21](=[O:23])[CH3:22])(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: COCOC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Under argon, a suspension of 0.5 g of sodium acetate in 60 ml of anhydrous chloroform, 2 ml of distilled phosphorus oxychloride, and 15 ml of methoxymethyl acetate is agitated for 30 minutes at a bath temperature of 60° C. After adding 2.0 g of 17α,21-diacetoxy-4-pregnene-3,20-dione, the mixture is further stirred for 3 hours at 70° C. and worked up analogously to Example 1. The dark crude product is purified on 200 g of silica gel with a hexane-ethyl acetate gradient (0-40% ethyl acetate), yielding 1.15 g of 17α,21-diacetoxy-6-methyl-4,6-pregnadiene-3,20-dione, mp 213°-215° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH2:23]([O:25][CH2:26][CH2:27]Br)[CH3:24].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH:8]=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][CH2:23][O:25][CH2:26][CH3:27])[CH:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOCCBr
Reactant: CCOC(=O)N1CC=C(c2c[nH]c3ncccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCn1cc(C2=CCN(C(=O)OCC)CC2)c2cccnc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.30 g (4.76 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid ethyl ester were dissolved in 11 ml of DMF and, at room temperature, 0.25 g (5.6 mmol) of 60% sodium hydride were carefully added. This mixture was stirred for half an hour at room temperature. 0.75 ml (6.0 mmol) of 2-bromoethyl ethyl ether were dropwise added and the stirring was continued for 24 hours at 60° C. The reaction mixture was cooled to room temperature and poured over cold water. This aqueous phase was extracted twice with dichloromethane and the organic phase was washed with water and brine, dried with magnesium sulphate, filtered and evaporated to dryness. The 1.46 g (74% of yield) of crude material were pure enough for the next synthetic step.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][N:11]([CH3:24])[C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[N:16]=1.[OH:25][C:26](=O)[CH2:27][N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[CH3:10][N:11]([CH3:24])[C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:26](=[O:25])[CH2:27][N:28]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[CH:19][CH:18]=2)[N:16]=1
Reactant: CN(C)c1nc(-c2ccc(N)cc2)cs1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)c1nc(-c2ccc(NC(=O)CN(Cc3ccccc3)C(=O)OC(C)(C)C)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
DIPEA (4.21 mL, 24.2 mmol) was added to a solution of N,N-dimethyl-4-(4-aminophenyl)-2-thiazolamine (1.77 g, 8.07 mmol, described in the previous section), tert-butyl N-(2-hydroxy-2-oxoethyl)-N-(phenylmethyl)carbamate {2.35 g, 8.87 mmol, described in example 2, section a)} and BOP (3.92 g, 8.87 mmol) in DMF (8 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h then diluted with EtOAc (300 mL). The solution was washed successively with H2O (2×60 mL), saturated aqueous NaHCO3 (60 mL) and brine (60 mL), dried (MgSO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, Hex:EtOAc:EtOH, 5:2:1) gave the title compound (3.13 g, 83% yield) as a beige solid: 1H NMR (400 MHz, DMSO-d6) δ9.98, 9.92 (2s, 1 H), 7.80 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.26-7.38 (m, 5H), 7.06 (s, 1H), 4.48 (s, 2H), 3.97, 3.86 (2s, 2H), 3.08 (s, 6H), 1.37 (s, 9H); MS (FAB) m/z 467 (MH)+; Anal. Calcd for C25H30N4O3S: C, 64.35; H, 6.48; N, 12.01. Found: C, 64.54; H, 6.56; N, 12.12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19](C=O)=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH2:35]([S:38]([CH2:41][CH2:42][NH2:43])(=[O:40])=[O:39])[CH2:36][CH3:37].[CH2:44](COC)OC>>[F:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[CH2:27][O:26][C:25]1[CH:24]=[CH:23][C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4([CH2:44][NH:43][CH2:42][CH2:41][S:38]([CH2:35][CH2:36][CH3:37])(=[O:40])=[O:39])[CH2:17][CH:18]=[CH:19][O:20]4)[CH:14]=3)[N:9]=[CH:8][N:7]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Reactant: CCCS(=O)(=O)CCN
Reactant: COCCOC
Product: CCCS(=O)(=O)CCNCC1(c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)CC=CO1

Procedure:
5-(4-{3-Chloro-4-[(3-fluorobenzyl)oxy]anilino}-6-quinazolinyl)-2-furaldehyde (0.32 mmol) and 2-n-propanesulphonyl-ethyl amine (0.95 mmol) were reacted together in dimethoxyethane as in Procedure D. 1H NMR (DMSO) 11.85 (bs, 1H); 9.94 (bs, 2H); 9.67 (s, 1H); 8.95 (s, 1H); 8.45 (d, 1H); 8.08 (s, 1H); 8.00 (d, 1H); 7.84 (d, 1H); 7.50 (m, 1H); 7.38 (m, 4H); 7.22 (m, 1H); 6.88 (s, 1H); 5.35 (s, 2H); 4.48 (s, 2H); 3.68 (m, 2H); 3.46 (m, 2H); 3.26 (m, 2H); 1.75 (m, 2H); 1.01 (m, 3H). Electrospray MS m/z 609 (MH+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][NH:31][CH3:32])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:49]([Cl:51])[Cl:50]>C(O)(=O)C>[NH3:1].[CH2:49]([Cl:51])[Cl:50].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][N:31]([CH3:32])[CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(CCN(C)Cc2ccc(OCCCN3CCCCC3)cc2)cc1OC
Product: N
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (214 mg), [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine (170 mg), and acetic acid (0.05 mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (300 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (350 mg). 1H NMR (400 MHz, CDCl3): 7.18 (d, J=8.6 Hz, 2H), 6.85-6.69 (m, 5H), 3.99 (t, J=6.3 Hz, 2H), 3.85 (s, 6H), 3.48 (s, 2H), 2.79-2.74 (m, 2H), 2.63-2.58 (m, 2H), 2.50-2.35 (m, 6H), 2.25 (s, 3H), 1.97 (m, 2H), 1.63-1.56 (m, 4H), 1.47-1.40 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3O[CH:8]3[C:7]=2[CH:15]=1)#[N:2].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[C:25]([O:27][CH2:28]C)=[O:26].[H-].[Na+].Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[C:8]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[C:17]3[C:25]([O:27][CH3:28])=[O:26])[C:7]=2[CH:15]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccccc2n1C1=CC(C)(C)Oc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of 6-cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-benzopyran (2.0 g, 9.95 mmol) (prepared according to Evans et al., J. Med. Chem., 1983, 26, 1582 and J. Med. Chem., 1986, 29, 2194), and indole-2-carboxylic acid, ethyl ester (2.25 g, 11.9 mmol) in dimethylforamide (10.0 mL) at 0° C. under argon was added sodium hydride (476 mg of 60% oil dispersion, 11.92 mmol) in portions. After the addition was finished, the reaction mixture was allowed to warm up to room temperature and then heated at 90° C. for 16 hours. It was cooled to 0° C. in ice bath and diluted with ethyl acetate. To the resulting solution was added 1N hydrochloric acid until pH~5. The organic layer was separated and the aqueous layer was reextracted with ethyl acetate. The combined organic extracts were washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue in dichloromethanemethanol (90:10) at 0° C. was treated with freshly prepared diazomethane. The reaction mixture was warmed up to room temperature and stirred for 1 hour. Few drops of acetic acid were added to decompose excess diazomethane (until reaction mixture turned colorless) and the solvent was evaporated to yield a brown oil It was purified by flash chromatography (dichloromethane) to yield the less polar 1-(6-cyano-2,2-dimethyl-2H-benzopyran-4-yl)-1H-indole-2-carboxylic acid, methyl ester (1.6 g). Further elution furnished the more polar title compound (380 mg) as a colorless solid, m.p. 197°-200° C. (isopropyl ether): IR (KBr) 2227, 1710, 1489, 1207 cm-1 : 1H NMR (DMSO-d6) δ 7.7 (m, 2 H), 7.47, 7.41 (s, 1 H), 7.15 (m, 3 H), 7.0, 6.85 (d, J=10 Hz, 1 H), 6.6 (m, 1 H), 5.75 (d, J=5.8 Hz, 1 H), 4.5, 4.2 (m, 2 H), 3.9, 3.5 (s, 3 H), 1.48, 1.45 (s, 3 H), 1.37, 1.27 (s, 3 H) (doubling of signals due to rotamers present in solution); 13C NMR (DMSO-d6) 162.1, 156.2, 136.3, 133.3, 131.9, 129.8, 126.9, 124.7, 123.4, 123.2, 120.6, 118.5, 112.5, 111.0, 103.3, 81.25, 68.84, 54.8, 51.9, 26.5, 18.25 ppm. The peaks due to the minor rotamer appear at 132.5, 125.2, 123.0, 122.3, 121.0, 117.8, 113.2, 71.4, 56.2, 51.6, 26.8, 22.8, 18.7 ppm.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[C:7]#[N:8].O.[CH:16]([NH2:18])=O>>[NH2:8][C:7]1[C:6]2[CH:5]=[C:4]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:3][C:2]=2[N:1]=[CH:16][N:18]=1
Reactant: N#Cc1cc(-c2ccccc2)oc1N
Reactant: NC=O
Solvent: O
Product: Nc1ncnc2oc(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of 2-amino-3-cyano-5-phenylfuran (9.18 g, 49.8 mmol) in formamide was heated to 180° C. After 3 hours, the solution was cooled to room temperature, poured into water (250 mL), and the resulting mixture filtered to afford 4-amino-6-phenylfuro-[2,3-d]pyrimidine (11.0 g, crude) as a brown solid. The solid was dissolved in acetic acid (150 mL) and bromine (6 mL, 18.7 g, 117 mmol) was added. The reaction mixture was then heated to 100° C. for 2 hours, cooled, and poured into sodium thiosulfate solution (250 mL, 0.5 N aq). 4-Amino-5-bromo-6-phenylfuro-[2,3-d]pyrimidine was then filtered off as a yellow solid (13.25 g, crude). A portion of this aminopyrimidine (4.48 g, crude, up to 15.4 mmol) was then dissolved in MeCN. Di-tert-butyl dicarbonate (7.00 g, 32.1 mmol) was added, followed by 4-(N,N)-dimethylaminopyridine (2.00 g, 16.4 mmol). The resulting solution was allowed to stir at room temperature for 3 days, and then concentrated in vacuo to a brown oil. Flash column chromatography (SiO2, EtOAc:hexane 1:6) afforded 4-di-tert-butyloxycarbonylamino-5-bromo-6-phenylfuro-[2,3-d]pyrimidine (2.39 g, 4.34 mmol) as an off-white powder.
Reaction SMILES: [N:1]1[N:2]([CH:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[N:1]1[N:2]([CH:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: CC(C)CC(C(=O)O)n1cc2ccccc2n1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC(C(=O)Nc1nccs1)n1cc2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of Compound 1 (640 mg, 2.76 mmol), 2-aminothiazole (284 mg, 2.76 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (1.0 g, 2.76 mmol) and 0.2 mL of Et3N in DMF (4 mL) was stirred at room temperature for 2 hours to provide the title compound, which was then purified by HPLC. 1H NMR (400 MHz, DMSO-d6) δ: 7.74 (d, J=12.0 Hz, 1H), 7.60 (d, J=12.0 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H), 7.25 (m, 2H), 7.05 (t, J=8.0, 8.0 Hz, 1H), 5.67 (m, 1H), 2.23 (m, 1H), 2.06 (m, 1H), 1.32 (m, 1H), 0.94 (d, J=8.0 Hz, 3H), 0.90 (d, J=8.0 Hz, 3H). [M+H] calc'd for C16H18OS, 314. found, 314.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][NH2:9])=[O:7].[CH2:14]1[C:23](=O)[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1.CCOCC>CO.C(O)(=O)C>[CH2:20]1[C:21]2[C:16](=[CH:15][CH:14]=[CH:23][CH:22]=2)[CH2:17][CH2:18][C:19]1=[N:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=1[CH3:13]
Reactant: COc1cccc(C(=O)NN)c1C
Reactant: O=C1CCc2ccccc2C1
Solvent: CCOCC
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc(C(=O)NN=C2CCc3ccccc3C2)c1C

Procedure:
3-Methoxy-2-methyl-benzoic acid hydrazide (1.0 g) and β-tetralone (0.9 g) were mixed in 4 ml of methanol with 1 drop of acetic acid at room temperature for 10 minutes. Approximately 10 mL of ether were added and the mixture was refrigerated. Crystals of 3-methoxy-2-methyl-benzoic acid (3,4-dihydro-1H-naphthalen-2-ylidene)-hydrazide formed, which were collected by filtration (0.85 g). 1H NMR (300 MHz, CDCl3) δ ppm): 6.8-7.3 (m, 4H), 3.75+3.8 (2 s, 3H), 3.45+3.7 (2 s, 2H), 2.85 (t, 2H), 2.4 (t, 2H), 2.27+2.25 (2 s, 3H); multiple conformers; Rf=0.56 (3:1 ethyl acctate:hexane); m.p.=138° C.; m.p. of 3-methoxy-2-methyl-benzoic acid hydrazide=113-116° C.
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:55])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:54])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42](=[O:53])[NH:43][C:44]4([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=5)[CH2:46][CH2:45]4)[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:57])[CH3:56])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].[C:59]([OH:65])([C:61]([F:64])([F:63])[F:62])=[O:60].CC#N>ClCCl>[C:59]([OH:65])([C:61]([F:64])([F:63])[F:62])=[O:60].[OH2:4].[CH:37]([C:33]1[C:34](=[O:36])[CH2:35][C@:23]2(/[CH:40]=[CH:41]/[C:42](=[O:53])[NH:43][C:44]3([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=4)[CH2:46][CH2:45]3)[CH2:22][CH2:21][C@:20]3([CH3:54])[C@H:25]([CH2:26][CH2:27][C@H:28]4[C@@:19]3([CH3:55])[CH2:18][CH2:17][C@@H:16]3[C@:29]4([CH3:32])[CH2:30][CH2:31][C@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:58])[C:3]([OH:5])=[O:4])[C:15]3([CH3:56])[CH3:57])[C:24]=12)([CH3:39])[CH3:38].[F:62][C:61]([F:64])([F:63])[C:59]([OH:65])=[O:60]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3ccccn3)CC2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3ccccn3)CC2)CC1=O
Product: O
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3a-((E)-3-oxo-3-((1-(pyridin-2-yl)cyclopropyl)amino)prop-1-en-1-yl)-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (460 mg, 0.577 mmol) in dichloromethane (6 mL) was added TFA (3 mL, 0.577 mmol). The reaction mixture was stirred at r.t for 2 hr and evaporated in vacuo to afford crude product, which was purified by preparative-HPLC (Mobile Phase: A=0.05% TFA/H2O, B=MeCN) to give the title compound, trifluoroacetic acid salt (30 mg, 0.033 mmol, 5.78%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=12.16 (br. s., 1H), 8.80 (s, 1H), 8.42 (d, J=4.0 Hz, 1H), 7.66 (t, J=7.4 Hz, 1H), 7.29-7.06 (m, 2H), 6.69 (d, J=15.8 Hz, 1H), 5.97 (d, J=15.8 Hz, 1H), 4.40 (dd, J=4.6, 10.9 Hz, 1H), 3.27-3.13 (m, 1H), 3.02-2.87 (m, 1H), 2.80 (d, J=11.5 Hz, 1H), 2.59-2.52 (m, 1H), 2.30-0.73 (m, 51H); LC/MS: m/z calculated 740.5. Found 741.3 (M+1)+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:3]=1.C(N(CC)CC)C.CN(C=O)C.[C:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)#[CH:46]>C(OCC)(=O)C.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>[C:47]1([C:45]#[C:46][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[N:9]=3)[N:4]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:3]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: C#Cc1ccccc1
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(-c2cnc3c(n2)c(C#Cc2ccccc2)cn3S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Temperature: 100 °C
Yield: 73.8 %

Procedure:
7-Iodo-5-(toluene-4-sulfonyl)-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (275 mg, 0.49 mmol), PdCl2(PPh3)2 (17 mg, 0.02 mmol), and cuprous iodide (5 mg, 0.02 mmol) were placed in a 5 ml microwave vial. The vial was capped and purged with nitrogen. Triethylamine (0.35 ml, 2.45 mmol) and 2.5 ml of DMF were added through the septum and the flask was purged again with nitrogen three times. Ethynyl-benzene (0.19 ml, 1.75 mmol) was added and the reaction was heated in a microwave reactor at 100° C. for 30 minutes. The crude reaction mixture was diluted with ethyl acetate, washed with water two times, dried and concentrated. The mixture was purified by flash chromatography using a gradient of 0% ethyl acetate in hexanes up to 30% to yield 195 mg of 7-phenylethynyl-5-(toluene-4-sulfonyl)-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine. MS: (M+H)+=540.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][N:10]2[CH2:11][CH2:12][CH:7]([O:6][C:5]3[CH:13]=[CH:14][C:15]([Cl:16])=[C:3]([Cl:2])[C:4]=3[CH3:17])[CH2:8][CH2:9]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1c(OC2CCNCC2)ccc(Cl)c1Cl
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1c(OC2CCN(CC3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc(Cl)c1Cl
Temperature: 20 °C
Reaction time: 14 h
Yield: 79.9 %

Procedure:
Acetonitrile (144 mL) and water (336 mL) were added to a mixture of 4-(3,4-dichloro-2-methyl-phenoxy)-piperidine hydrochloride (60 g), 4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (74.7 g) and potassium carbonate (57.3 g) and the mixture was heated to reflux for 7 h, then cooled over 30 min to 75° C. and held at 75° C. for 14 h, then heated over 30 min to reflux. Acetonitrile (192 mL) was added and then the mixture was cooled to 20° C. over 2 h to give a suspension. The suspension was filtered under vacuum, the filter cake was washed with water (180 mL) and then with acetonitrile (180 mL) and dried under vacuum at 40° C. to give 4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (73.9 g).