Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH2:13][C:14](=O)[CH3:15])(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH3:17][C:18]1[CH:22]=[C:21]([NH2:23])[NH:20][N:19]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH:28]=O>C1COCC1.N1CCCCC1>[Cl:24][C:25]1[CH:26]=[C:27]([CH:28]2[N:20]3[N:19]=[C:18]([CH3:17])[CH:22]=[C:21]3[NH:23][C:14]([CH3:15])=[C:13]2[S:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:12])=[O:11])[CH:30]=[CH:31][C:32]=1[Cl:33]
Reactant: COc1ccc(NS(=O)(=O)CC(C)=O)cc1
Reactant: Cc1cc(N)[nH]n1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: COc1ccc(NS(=O)(=O)C2=C(C)Nc3cc(C)nn3C2c2ccc(Cl)c(Cl)c2)cc1
Temperature: 70 °C
Reaction time: 36 h

Procedure:
N-(4-Methoxyphenyl)-2-oxopropane-1-sulfonamide (100 mg, 0.41 mmol, from Step C), 3-methyl-1H-pyrazol-5-amine (40 mg, 0.41 mmol) and 3,4-dichlorobenzaldehyde (72 mg, 0.41 mmol) were dissolved in THF (6 mL), to which was added a catalytic amount of piperidine (3 drops). The reaction in a sealed tube was stirred at 70° C. for about 36 hrs. After cooling to rt., solvent was removed and crude product was purified by HPLC (acetonitrile-water, 5% to 95% gradient) to provide pure product 7-(3,4-dichlorophenyl)-N-(4-methoxyphenyl)-2,5-dimethyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-sulfonamide as a solid. LC-MS found: (M+1)+=479.21.
Reaction SMILES: N#N.[Br:3][C:4]1[CH:5]=[C:6]([C:9](=[O:11])[CH3:10])[S:7][CH:8]=1.COC([O:17][CH3:18])OC.[C:19]([O-])(O)=O.[Na+]>C(O)CO>[Br:3][C:4]1[CH:5]=[C:6]([C:9]2([CH3:10])[O:17][CH2:18][CH2:19][O:11]2)[S:7][CH:8]=1
Reactant: COC(OC)OC
Reactant: CC(=O)c1cc(Br)cs1
Reactant: O=C([O-])O
Agent: N#N
Agent: [Na+]
Solvent: OCCO
Product: CC1(c2cc(Br)cs2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 1-(4-bromo-2-thienyl)ethan-1-one (2.00 g, 9.75 mmol) in ethylene glycol (10.7 mL) was treated with trimethylorthoformate (2.14 mL, 19.51 mmol) followed by LiBF4 (150 mg, 1.60 mmol). The reaction mixture was heated at 95° C. overnight. Sat. aq. NaHCO3 (20 mL) was added and the mixture was extracted with EA (20 mL). The org. extracts were washed with brine (2×20 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:80 EA-Hept) gave the title compound as a white solid. TLC: rf (20:80 EA-Hept)=0.50. LC-MS-conditions 02: tR=0.99 min.
Reaction SMILES: C1(S([C:10](=[CH:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=2)[C:11]([NH:13][CH3:14])=[O:12])(=O)=O)C=CC=CC=1.[N-:31]=[N+:32]=[N-:33]>>[CH3:30][C:27]([C:18]1[CH:17]=[C:16]([C:15]2[NH:31][N:32]=[N:33][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[CH:21]=[C:20]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:19]=1[OH:26])([CH3:28])[CH3:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CNC(=O)C(=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)S(=O)(=O)c1ccccc1
Product: CNC(=O)c1nn[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
reacting the product of step b) with a metal azide to yield 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-3H-[1,2,3]triazole-5-carboxamide.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[N:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([NH:23][C:24](=[O:26])[CH3:25])=[N:20][C:19]=2[CH3:27])=[CH:14][C:13]=1[Cl:28]>N1C=CC=CC=1>[Cl:28][C:13]1[CH:14]=[C:15]([C:18]2[S:22][C:21]([NH:23][C:24](=[O:26])[CH3:25])=[N:20][C:19]=2[CH3:27])[CH:16]=[N:17][C:12]=1[NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(N)c(Cl)c2)s1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(C)c(-c2cnc(NS(=O)(=O)c3ccccc3)c(Cl)c2)s1
Temperature: 25 °C

Procedure:
Phenylsulfonyl chloride (0.108 mL) was added to a stirred solution of N-[5-(6-amino-5-chloropyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (80 mg) in pyridine (1 mL) and the resultant solution was heated to 50° C. for 4 hours. The mixture was cooled to room temperature and concentrated by evaporation. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol as eluent. The material so obtained was triturated under diethyl ether. There was thus obtained the title compound as a white solid (38 mg); 1H NMR Spectrum: (DMSOd6) 2.13 (s, 3H), 2.29 (s, 3H), 7.60 (m, 2H), 7.75 (m, 1H), 7.98 (s, 1H), 8.02 (d, 2H), 8.18 (br s, 1H), 10.95 (br s, 1H); Mass Spectrum: M+H+ 423.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=O)[N:6]2[N:10]=[CH:11][CH:12]=[C:5]2[N:4]=1.P(Cl)(Cl)([Cl:15])=O.C(N(CC)CC)C>C(#N)C>[Cl:15][C:7]1[N:6]2[N:10]=[CH:11][CH:12]=[C:5]2[N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc2ccnn2c(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSc1nc(Cl)n2nccc2n1
Yield: 71 %

Procedure:
In a round bottom flask equipped with a magnetic stirbar, 2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (1.0 eq, 10.43 g, 57.24 mmol) was suspended in acetonitrile (100 ml). Phosphorus oxychloride (4.0 eq, 21 ml, 229.4 mmol) and triethylamine (1.05 eq, 8.4 ml, 60.27 mmol) were added and the mixture stirred at reflux for 3.5 hours, at which time LCMS indicated completion of the reaction. The mixture was cooled down and slowly poured into crushed ice (final total volume of about 600 ml). The solid was filtered, washed with water and dried in a vacuum oven to afford 4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine as a tan solid (8.15 g, 71% yield). LCMS (ES): >97% pure, m/z 201 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][CH:4]=1>Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:10])=[CH:7][N:8]=1
Reactant: COc1ccc(C=O)cn1
Agent: Cl
Product: O=Cc1ccc(O)nc1

Procedure:
A stirred solution of 6-methoxy-3-pyridinecarboxaldehyde (0.45 g, 3.3 mMol) in 3N HCl (10 mL) was heated to 100° C. for 30 minutes. Upon cooling, needle-like crystals developed. The crystals were collected via filtration to yield 17-2. 1H-NMR (CD3OD) δ 9.64 (s, 1H), δ 8.17-8.16 (m, 1H), S 7.96-7.94 (m, 1H), δ 6.58 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([O-:34])=[O:33].[Na+]>>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1)(=[O:33])=[O:34]
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Reactant: O=S([O-])c1ccc2ccccc2c1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4ccc5ccccc5c4)cc3c2C1
Yield: 85 %

Procedure:
The product of Example 29, step B and sodium 2-naphthylsulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 80:20 hexane/ethyl acetate) provided tert-butyl 8-(2-naphthylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (450 mg, 85%) as an orange solid: 1H NMR (CDCl3, 300 MHz) δ 8.58 (s, 1H), 8.14 (s, 1H), 8.02-7.82 (m, 5H), 7.66-7.56 (m, 2H), 7.50 (d, J=8.7 Hz, 1H), 4.57 (s, 2H), 3.82 (t, J=5.4 Hz, 2H), 2.90-2.80 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([S:9]([NH:12][CH2:13][C:14]2[C:15]([NH:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[C:16]3[CH:24]=[N:23][N:22]([CH2:25][CH3:26])[C:17]3=[N:18][C:19]=2[CH2:20][CH3:21])(=[O:11])=[O:10])=[CH:4][C:3]=1[C:34]([NH:36][CH2:37][C:38]1[CH:39]=[CH:40][C:41]([F:65])=[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][N:51]3[CH2:56][CH2:55][N:54](C(OC(C)(C)C)=O)[C@@H:53]([CH3:64])[CH2:52]3)[CH:45]=2)[CH:43]=1)=[O:35]>O1CCOCC1.CO.Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([S:9]([NH:12][CH2:13][C:14]2[C:15]([NH:27][CH:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[C:16]3[CH:24]=[N:23][N:22]([CH2:25][CH3:26])[C:17]3=[N:18][C:19]=2[CH2:20][CH3:21])(=[O:11])=[O:10])=[CH:4][C:3]=1[C:34]([NH:36][CH2:37][C:38]1[CH:43]=[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][N:51]3[CH2:56][CH2:55][NH:54][C@@H:53]([CH3:64])[CH2:52]3)[CH:45]=2)[C:41]([F:65])=[CH:40][CH:39]=1)=[O:35]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNS(=O)(=O)c1cc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c(Cl)cc1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNS(=O)(=O)c1cc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2)c(Cl)cc1F
Temperature: 60 °C
Yield: 75.4 %

Procedure:
345(c) The 1,1-dimethylethyl (2S)-4-[(5′-{[({2-chloro-5-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)sulfonyl]-4-fluorophenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate was dissolved in 2 mL of dioxane:MeOH (3:1). Three drops of HCl (concentrated) were added to the resultant solution and heated at 60° C. for 1 h. The solution was applied to the amine column, rinsed with 10 mL of dioxane:MeOH (3:1) to afford 63.0 mg (75.4%) the title compound. LC-MS m/z 837 (M+H)+, 1.29 min (ret time).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].CC1C(C2SC(C(N3CCC[C@@H](NC(=O)C)C3)=O)=CC=2)=NOC=1C(F)(F)F.[CH3:46][N:47]([CH2:55][C@@H:56]1[CH2:61][CH2:60][CH2:59][NH:58][CH2:57]1)C(=O)OC(C)(C)C.[ClH:62]>O1CCOCC1.C(N(CC)CC)C.C1COCC1>[ClH:62].[CH3:46][NH:47][CH2:55][C@@H:56]1[CH2:61][CH2:60][CH2:59][N:58]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:57]1
Reactant: CN(C[C@@H]1CCCNC1)C(=O)OC(C)(C)C
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: CC(=O)N[C@@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CNC[C@@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1
Reaction time: 4 h
Yield: 88 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and tert-butyl methyl[(3R)-piperidin-3-ylmethyl]carbamate (Preparative Example 33, 298 mg, 1.30 mmol) by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride (0.90 eq) was added to a THF solution of triethylamine and and tert-butyl methyl[(3R)-piperidin-3-ylmethyl]carbamate. The reaction was allowed to stir 4 hr then partitioned between EtOAc (10 mL) and a 1 N aqueous HCl solution (10 mL). The organic portion was washed with a further portion of 1N HCl solution (10 mL) followed by a saturated aqueous NaHCO3 solution (10 mL) and brine (10 mL). The organic layer was then dried over MgSO4, filtered, and evaporated to a residue that was chromatographed on silica gel with EtOAc/hexane (40% then 60%) as eluant to afford Boc-protected intermediate as a yellow-tinted oil (423 mg, 67%). LC/MS 7.44 min, [M+1]+ 487. The intermediate was then treated with a 4 N solution of hydrogen chloride in 1,4-dioxane (4 mL) and stirred for 24 hr, after which time the reaction mixture was evaporated in vacuo to afford a free-flowing colorless powder (320 mg, 88%). LC/MS 4.91 min, [M+1]+ 388.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[C:15]([C:18](O)=[O:19])[CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:21]([N:24]([CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[CH2:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C[CH2:56][N:57]=[C:58]=NCCCN(C)C.CNC.CCN(C(C)C)C(C)C>CN(C=O)C>[C:41]([O:40][C:38](=[O:39])[NH:37][CH2:36][CH2:35][CH2:34][N:24]([CH:21]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2=[C:15]([C:18](=[O:19])[N:57]([CH3:58])[CH3:56])[CH:16]=[CH:17][N:11]2[N:10]=1)[CH2:22][CH3:23])[C:25](=[O:33])[C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)([CH3:43])([CH3:42])[CH3:44]
Reactant: CCC(c1nn2ccc(C(=O)O)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(c1nn2ccc(C(=O)N(C)C)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.1 %

Procedure:
A mixture of 3-benzyl-2-{1-[(3-tert-butoxycarbonylamino-propyl)-(4-methyl-benzoyl)-amino]-propyl}-4-oxo-3,4-dihydro-pyrrolo[2,1-f]-[1,2,4]triazine-5-carboxylic acid (0.0029 g, 0.0048 mmol), HOBt (0.0013 g, 0.0097 mmol), EDCI (0.002 g, 0.0097 mmol), dimethylamine (2 M in THF, 0.024 ml, 0.048 mmol) and DIPEA (0.003 mL, 0.019 mmol) in DMF (0.5 mL) were stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum, dissolved in EtOAc (3 mL). The organic solution was washed with 10% LiCl (3×2 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 3/1 hexane/EtOAc to afford title compound as a solid (0.001 g, 33%): MS (ESI+) 629 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3[C:11](=[CH:12][C:13]4[O:17][CH:16]=[N:15][C:14]=4[C:18]=3[F:20])[NH:10][C:9]2=[O:21])=[C:4]([Cl:22])[CH:3]=1.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3[C:11](=[CH:12][C:13]4[O:17][CH:16]=[N:15][C:14]=4[C:18]=3[F:20])[N:10]([S:33]([CH:30]3[CH2:32][CH2:31]3)(=[O:35])=[O:34])[C:9]2=[O:21])=[C:4]([Cl:22])[CH:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: O=c1[nH]c2cc3ocnc3c(F)c2n1-c1ccc(Br)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1n(-c2ccc(Br)cc2Cl)c2c(F)c3ncoc3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of 5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (100 mg, 0.26 mmol) in CH2Cl2 (10 mL) was added triethylamine (80 mg, 0.78 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (55 mg, 0.39 mmol) and DMAP (10 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (15 mL×2). The combined organic phase was washed with water (15 mL) and brine (20 mL) successively, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (110 mg, 86.5% yield). 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.71-7.69 (m, 2H), 7.32 (m, 1H), 3.35 (m, 1H), 1.69 (m, 2H), 0.88 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[C:15]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)[CH:14]=[CH:13][C:3]=1[CH2:4]NC(=O)OC(C)(C)C.[C:23](=[O:26])([O-:25])[O-].[K+].[K+].[CH2:29]([O:36][C:37](=[O:40])[CH2:38]Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CN(C=O)C>[C:3]([O:25][C:23]([CH2:4][C:3]1[CH:13]=[CH:14][C:15]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[CH:16][C:2]=1[NH:1][CH2:38][C:37]([O:36][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:40])=[O:26])([CH3:13])([CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(-c2ccc(CNC(=O)OC(C)(C)C)c(N)c2)no1
Reactant: O=C(CBr)OCc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc(CC(=O)OC(C)(C)C)c(NCC(=O)OCc3ccccc3)c2)no1
Temperature: 80 °C
Yield: 165.4 %

Procedure:
To a solution of compound 58b (0.57 g, 1.88 mmol) and potassium carbonate (0.519 g, 3.76 mmol) in DMF (6 mL) in a pressure tube was added benzyl-2-bromoacetate (0.447 mL, 2.8 mmol). The reaction mixture was heated at 80° C. overnight, then cooled to rt. Water was added, and the mixture was extracted with ethyl acetate (3×). The combined organics were washed with water and brine, dried, and concentrated. The residue was purified by silica gel chromatography using a gradient from 10 to 30% ethyl acetate in hexanes to give compound 58c (0.68 g, 80%) as a clear oil. ESI-MS m/e 453.5 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[O:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1>O>[CH3:7][CH2:8][CH2:9][CH2:10][O:6][C@H:9]([CH2:10][OH:6])[CH2:8][CH3:7]
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCO[C@@H](CC)CO
Temperature: 10 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
In the same reaction apparatus as in Example 15, 100 g of 25% fuming sulfuric acid was dropped into 500 g of tetrahydrofuran at -20° C. over 40 minutes, and then the resulting mixture was subjected to reaction at -20° C. for 2 hours. The conversion at this point was 31%. Then the reaction mixture was heated to 10° C. and subjected to reaction for 2 hours, after which 10 g of water was added to the mixture to terminate the polymerization. The final conversion was 58%. Thereafter, 400 g of water was added to the polymerization mixture, and the dropping funnel was replaced by the distilling column, after which the contents in the flask were heated and hydrolyzed in an oil bath at 100° C. with stirring for 2 hours while distilling off and recovering unreacted tetrahydrofuran. Then, the contents in the flask were allowed to stand at 100° C. to cause separation of layers and the aqueous layer was withdrawn. To the obtained PTMG layer were again added 230 g of water and 20 g of the withdrawn aqueous layer, and the resulting mixture was refluxed with heating and hydrolyzed in an oil bath at 120° C. with stirring for 2 hours and then allowed to stand at 100° C. to cause separation of layers, after which the separated aqueous layer was withdrawn. The amount of residual sulfuric ester groups in PTMG was 5 ppm and the acid number was 0.21. To the resulting PTMG layer was further added 250 g of water having suspended therein 0.25 g of basic magnesium carbonate, and the resulting mixture was subjected to heating and washing treatment in an oil bath at 100° C. for one hour while stirring the mixture vigorously, after which the mixture was allowed to stand to cause separation of layers. The mixture was not emulsified throughout the treatment, and upon allowing the mixture to stand, the mixture underwent separation of layers in a very short time, and the PTMG layer after the separation of layers was almost transparent. After removing the aqueous layer, the PTMG layer was subjected to perfect evaporation of volatile matters under reduced pressure at 80° C., and then filtered through a 10-μ mesh membrane filter to obtain 260 g of colorless transparent PTMG (yield: 52%). The thus obtained PTMG was analyzed to determine its number-average molecular weight, hydroxyl number, acid number, and amount of residual sulfuric ester groups, all of which are shown in Table 3.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=[O:12].[Na+].[Na+].CN[C@@H]1CCCC[C@H]1NC.Cl>CN[C@@H]1CCCC[C@H]1NC.O>[C:4]([OH:6])(=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:12]
Reactant: O=C(O)c1ccccc1Br
Reactant: O=C([O-])[O-]
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
Under nitrogen, 2.00 g (9.95 mmol) of 2-bromobenzoic acid was combined with 10 g of H2O. 1.11 g (10.45 mmol) of Na2CO3 was then added. The mixture was heated to reflux with stirring for 30 min, remaining under a nitrogen atmosphere. Another 1.58 g (14.92 mmol) of Na2CO3 was added to the reaction mixture and reflux was continued for 30 min. Separately, 22 mg of CuBr2 and 28 mg of rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (Ligand F) were combined with 2 mL H2O under nitrogen to give a deep purple solution. This solution was added to the stirred reaction mixture via syringe at 80° C. under nitrogen and stirred for 1 h at 80° C. After cooling to 25° C., the reaction mixture was acidified with 15% HCl, producing a white precipitate. The white precipitate was filtered and washed with water. After drying, a total of 1.34 g (9.7 mmol, 98% yield) salicylic acid was collected. The purity was determined by 1H NMR to be about 99%.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:8][C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:5]=1)[CH3:2].C(OCC)C.[Cl:20]NC(=O)CCC(N)=O>O1CCOCC1>[ClH:20].[Cl:20][C:5]1[N:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:8][C:4]=1[NH:3][CH2:1][CH3:2]
Reactant: CCNc1cnc(-c2cccnc2)s1
Reactant: NC(=O)CCC(=O)NCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCNc1sc(-c2cccnc2)nc1Cl
Product: Cl
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a dry 500 ml round bottom flask equipped with magnetic stirrer, thermometer, and nitrogen inlet was charged N-ethyl-2-(pyridin-3-yl)thiazol-5-amine (5.1 g, 25 mmol), diethyl ether (200 mL) and dioxane (5 mL). The resulting suspension (not all solid dissolved) was cooled to 5° C., and N-chlorosuccinamide (3.65 g, 27.3 mmol) was added portionwise. After all of the chlorinating agent was added, a brown solid precipitated from solution. The reaction mixture was stirred at 5° C. for 60 minutes, then analyzed by HPLC(YMC AQ column 5% ACN 95% water-0.05% TFA to 95% ACN 5% water with 0.05% TFA over 20 Min @ 1.0 ml/min). HPLC analysis showed no starting material and one major product consistent with the desired chloride. The brown suspension was filtered through a pad of Celite®, and the Celite® pad rinsed with diethyl ether (˜20 mL). The filtrate was cooled to 5° C. and acidified with stirring by the addition of 6.5 ml of 4M HCl in dioxane. A yellow solid immediately formed. The solid was collected by vacuum filtration, rinsed with diethyl ether, and dried in vacuo at 40° C. for 2 hours. This gave 4-chloro-N-ethyl-2-(pyridin-3-yl)thiazol-5-amine hydrochloride as a yellow solid (6.3 g, 92%): mp 180-182° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J=2.0 Hz, 1H), 8.70 (dd, J=5.4, 1.3 Hz, 1H), 8.59-8.42 (m, 1H), 7.86 (dd, J=8.2, 5.3 Hz, 1H), 5.27 (s, 5H), 3.20 (q, J=7.2 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 148.10, 140.19, 138.58, 137.91, 137.01, 132.06, 127.30, 115.89, 43.43, 13.87; Anal. Calcd. for C10H11Cl2N3S: C, 43.49; H, 4.01; Cl, 25.67; N, 15.21; S, 11.61. Found: C, 43.42: H, 4.01; Cl, 25.55; N, 14.99; S, 11.46.
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH2:24][C@H:25]2[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[O:26]2)=[CH:21][C:5]2[C:6]([CH3:20])([CH3:19])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([Cl:18])[CH:10]=4.C(=O)([O-])[O-:33].[Cs+].[Cs+].C1(P(C2CCCCC2)[C:45]2C=CC=C[C:46]=2[C:51]2[C:56](C(C)C)=CC(C(C)C)=C[C:52]=2C(C)C)CCCCC1>[Pd](Cl)Cl.C(#N)C.C(#N)C.C(#N)C>[Cl:18][C:11]1[CH:10]=[C:9]2[C:14]([C:15]3[C:16](=[O:17])[C:4]4[CH:3]=[C:2]([C:45]#[C:46][C:51]([OH:33])([CH3:56])[CH3:52])[C:22]([O:23][CH2:24][C@H:25]5[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[O:26]5)=[CH:21][C:5]=4[C:6]([CH3:20])([CH3:19])[C:7]=3[NH:8]2)=[CH:13][CH:12]=1
Reactant: CC1(C)OC[C@H](COc2cc3c(cc2Br)C(=O)c2c([nH]c4cc(Cl)ccc24)C3(C)C)O1
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl[Pd]Cl
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(O)C#Cc1cc2c(cc1OC[C@H]1COC(C)(C)O1)C(C)(C)c1[nH]c3cc(Cl)ccc3c1C2=O
Temperature: 80 °C
Reaction time: 12 h
Yield: 689 %

Procedure:
To the mixture of 9-bromo-3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S7-1, 50 mg, 0.1 mmol), bis(acetonitrile) palladium (II) dichloride (2.6 mg, 0.01 eq.), cesium carbonate (195 mg, 6 eq.) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (14.3 mg, 0.03 eq.), acetonitrile (2 mL) was added and stirred at 80° C. for 12 hr. Tar-like residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain 3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-9-(3-hydroxy-3-methyl-but-1-ynyl)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (brown powder, 105 mg).