Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N+:11]([O-])([O-:13])=[O:12].[K+]>OS(O)(=O)=O>[N+:11]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH2:3][CH2:2][C:1]2=[O:10])([O-:13])=[O:12]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1CCc2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1CCc2c1cccc2[N+](=O)[O-]
Reaction time: 1 h
Yield: 17.7 %

Procedure:
To a 0° C. solution of indanone (1.1 mL, 9.16 mmol, 1.0 equiv) in concentrated H2SO4 (9 mL) was added KNO3 (926 mg, 9.16 mmol, 1.0 equiv) as a solid in several portions over 5 min. After stirring for 1 h, the reaction mixture was poured onto ice. The aqueous suspension was extracted with EtOAC (3×30 mL), and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (20%-50% EtOAc/Hexanes) provided the desired compound as a yellow solid (288 mg, 18%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[Cl:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:25][C:24]3[CH:26]=[C:20]([O:19][CH3:18])[CH:21]=[CH:22][C:23]=3[CH3:27])=[C:3]([C:16]#[N:17])[CH:4]=[N:5]2)=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1ccc(C)c(N)c1
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1ccc(C)c(Nc2c(C#N)cnc3cc(Cl)c([N+](=O)[O-])cc23)c1
Temperature: 115 °C
Yield: 62.1 %

Procedure:
A mixture of 0.9 g (3.36 mmol) of 4,7-dichloro-6-nitro-3-quinolinecarbonitrile, 0.55 g (4.0 mmol) of 5-methoxy-2-methylaniline, 0.46 g (4.0 mmol) of pyridine hydrochloride in 10.0 mL of 2-ethoxyethanol is heated at 115° C. for 1 hour, cooled and poured into a saturated solution of sodium bicarbonate. The oil is extracted with methylene chloride, dried over anhydrous sodium sulfate and the solvent is evaporated to yield a foam. This is purified by silica gel chromatography, eluting with methylene chloride/methanol (99.5:0.5) to yield 0.77 g of 7-chloro-4-(5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile as a yellow solid, mp 180–182° C.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([CH3:23])[CH3:22])[CH:13]=2)=[CH:8][CH:7]=1.P(Cl)(Cl)(Cl)=O.O>C(#N)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([CH3:23])[CH3:22])[C:13]=2[CH:4]=[CH:3][CH:1]=[O:2])=[CH:8][CH:7]=1
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Reactant: C=CC=O
Solvent: O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)n1c(C=CC=O)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Use of the crude acrolein coming from Example 4a. To a suspension of 3-[3-(4-Fluorophenyl)-1-(1-Methylethyl)-1H-Indole (130.7 g), phosphorus oxychloride (114.6 g) in acetonitrile (128 ml) cooled at 5° C. a solution of crude acrolein (116.9 g from Example 4a) in acetonitrile (145 ml) is added dropwise in 60 minutes. The reaction mixture is then warmed to 60° C. and kept under stirring at 60° C. for 6 hours; water (1100 ml) is added and after 1 hour at 60° C. the formed solid is filtered on Buchner and washed with water (250 ml×3). The wet solid (131 g) is dissolved in toluene (1050 ml), celite (2.7 g) and charcoal (4 g) are added and the mixture is stirred at room temperature for 30 minutes. After filtration of the solid, the mixture is washed with water (500 ml×2), the phases are separated, the organic solvent is distilled off at reduced pressure and the residue is dissolved at 75° C. with isopropanol (260 ml). The solution is cooled at 10° C. and stirred for 1 hour. The precipitate is filtered on Buchner, washed with isopropanol (60 ml×3) and dried at 60° C. under vacuum. 84.2 g (53% molar yield) of the product are obtained.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[C:13]3[C:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[CH:25]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:4]1O)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[C:13]3[C:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[CH:25]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCC1Cc2c(-c3cc4ccccc4c4ccccc34)cccc2C1O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1=Cc2c(cccc2-c2cc3ccccc3c3ccccc23)C1
Reaction time: 4 h
Yield: 82.6 %

Procedure:
A 300-ml three-necked round flask equipped with a stirring bar, a Dimroth condenser, a dropping funnel and a thermometer was charged with 12.3 g (36.3 mmol) of 2-ethyl-1-hydroxy-4-(9-phenanthryl)indane, 19.7 ml (142 mmol) of triethylamine and 61.5 ml of methylene chloride. To the mixture was gradually dropwise added a solution containing 3.3 ml (42.6 mmol) of methansulfonyl chloride dissolved in 5 ml of methylene chloride under a nitrogen atmosphere at 0° C. After the addition was completed, the temperature was elevated to room temperature, and the reaction mixture was stirred for additional 4 hours. To the reaction mixture was added 80 ml of a saturated aqueous solution of sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted with 50 ml of methylene chloride two times. The combined organic phase was washed with water, and then a saturated aqueous solution of sodium chloride, followed by drying over anhydrous Na2SO4. The solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel (eluting with hexane, and hexane/ethyl acetate (100/3 parts by volume)) to give 9.61 g of the desired product (mixture of two isomers) as a pasty pale yellow-green liquid (yield: 83%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:37]=[C:38]([NH:39][C:12]([NH:11][C:4]2[CH:5]=[C:6]([C:7]([F:8])([F:9])[F:10])[N:2]([CH3:1])[N:3]=2)=[O:20])[CH:40]=[CH:41][CH:42]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: Cn1nc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)n(C)n4)c3)c2cc1OC
Temperature: 50 °C
Yield: 21 %

Procedure:
Using the procedure described in Example 159B, phenyl 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate from the previous step (0.114 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) were heated at 50° C. for 3 hours, to afford 1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]urea as solid (0.041 g, 21%). 1H NMR (300 MHz, CDCl3) δ 9.6 (br, 1H), 8.65 (s, 1H), 7.63 (m, 1H), 7.61 (s, 1H), 7.43 (t, 1H), 7.33 (m, 2H), 7.02 (dd, 1H), 6.92 (s, 1H), 6.25 (s, 1H), 4.08 (s, 6H), 3.93 (s, 3H); LC-MS (ESI) m/z 489 (M+H)+.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7]1(=[O:21])=[O:20])=[CH:18][CH:17]=[CH:16][CH:15]=3.C(O)(C)(C)C.Cl>CO>[CH3:2][O:3][C:4]([C:5]1[NH:6][S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:22]
Reactant: COC(=O)CN1C(=O)c2ccc3ccccc3c2S1(=O)=O
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CC(C)(C)O
Product: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Temperature: 60 °C

Procedure:
0.90 mol of methanol-free sodium methylate was prepared by dissolving 20.7 gm (0.90 gm-atom) of sodium in 350 ml of absolute methanol, subsequently distilling off the alcohol, and repeated azeotropic distillation with xylene. After addition of 9.15 gm (0.30 mol) of 3-oxo-naphth[2,1-d]isothiazoline-2-acetic acid methyl ester-1,1-dioxide, 250 ml of anhydrous tert.butanol were added. The reaction mixture was slowly heated to 60° C, kept at 60°-65° C for 11/4 hours, and subsequently refluxed for 1 hour. The mixture was allowed to cool, was then decomposed with ice and adjusted to a pH-value of 3-4 with concentrated hydrochloric acid. The solid product which formed was suction-filtered off, washed with water and dried, yielding 72.0 gm (78% of theroy) of 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1 -dioxide, m.p. 218°-220° C (after recrystallizing twice from ethylene chloride).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH:35]([CH3:38])[CH2:36][CH3:37]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH:35]([CH3:38])[CH2:36][CH3:37])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CCC(C)CBr
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CCC(C)CN1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 43.1 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and 1-bromo-2-methyl butane (103 mg, 0.690 mmol) gave 7-cyclopentyl-2-{5-[4-(2-methyl-butyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 42%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=1)=[O:12].CN1C2C(=CC=CC=2)C=C1C(O)=O.CC1(C)C(C)(C)OB(C2C=CC(N)=CC=2)O1.Br[C:59]1[N:60]=[C:61]([C@H:69]2[CH2:74][CH2:73][C@H:72]([N:75]3[CH2:80][CH2:79][N:78]([CH3:81])[CH2:77][CH2:76]3)[CH2:71][CH2:70]2)[N:62]2[CH:67]=[CH:66][N:65]=[C:64]([CH3:68])[C:63]=12>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:59]2[N:60]=[C:61]([C@H:69]3[CH2:74][CH2:73][C@H:72]([N:75]4[CH2:80][CH2:79][N:78]([CH3:81])[CH2:77][CH2:76]4)[CH2:71][CH2:70]3)[N:62]3[CH:67]=[CH:66][N:65]=[C:64]([CH3:68])[C:63]=23)=[CH:16][CH:15]=1)=[O:12]
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Reactant: Cn1c(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc2ccccc21
Agent: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: Cn1c(C(=O)O)cc2ccccc21
Product: Cc1nccn2c1c(-c1ccc(NC(=O)c3cc4ccccc4n3C)cc1)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1

Procedure:
Reaction of 1-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indole-2-carboxamide (29 mg), prepared from 1-methyl-1H-indole-2-carboxylic acid which was transformed into its acid chloride first and then reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, and 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (30 mg) according to the procedure described in example 4 step 4c and purification by column chromatography (silica gel; dichloromethane with gradient 0 to 20% of methanol) gave 1-methyl-N-(4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1H-indole-2-carboxamide (12 mg)
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([N+:26]([O-:28])=[O:27])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19].CN(C)C=[O:32]>C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([N+:26]([O-:28])=[O:27])[C:23]=1[O:24][CH3:25])[C:18]([O:32][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:3](=[O:4])[CH3:2])=[O:19]
Reactant: O=C(CO)c1ccccc1
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)Oc2ccccc2C(C)=O)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 11.25 g of 2-hydroxyacetophenone in 100 ml of absolute dimethylformamide is added dropwise under an argon atmosphere within 15 minutes to a suspension of 3.6 g of a 55 percent sodium hydride dispersion in 50 ml of absolute dimethylformamide and the mixture is stirred at room temperature for 1 hour. After cooling to 0°, a solution of 20.3 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 100 ml of absolute dimethylformamide is added dropwise thereto within 20 minutes and the mixture is stirred at room temperature overnight. The reaction mixture is poured into ice-water, whereupon the mixture is extracted twice with 250 ml of ethyl acetate each time. The organic phase is extracted twice with 100 ml of sodium chloride solution each time, dried over sodium sulfate and evaporated. The brown oil obtained is heated in 100 ml of toluene. The separated precipitate is filtered under suction and the filtrate is chromatographed on a 30-fold amount of silica gel with toluene/ethyl acetate (4:1). After recrystallization from ethyl acetate/hexane there is obtained o-acetylphenyl 3,4-dimethoxy-5-nitrobenzoate in the form of yellowish crystals of m.p. 108°-109°.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:13](=O)[CH2:12][N:11]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H]1C=C(COCC2C=CC(OC)=CC=2)C(O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C.[CH2:69]([O:72][NH:73][S:74]([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=1[N+:83]([O-:85])=[O:84])(=[O:76])=[O:75])[CH:70]=[CH2:71].C(ON([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO[Si](C(C)(C)C)(C)C)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:69]([O:72][N:73]([CH:13]1[CH2:12][N:11]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH:15]=[C:14]1[CH2:16][O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[S:74]([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=1[N+:83]([O-:85])=[O:84])(=[O:76])=[O:75])[CH:70]=[CH2:71]
Reactant: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: COc1ccc(COCC2=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC2=O)cc1
Agent: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: COc1ccc(COCC2=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC2O)cc1
Product: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1COCc1ccc(OC)cc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (S)-tert-butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(((4-methoxybenzyl)-oxy)methyl)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 169, 17.10 g, 34.78 mmol) and N-(allyloxy)-2-nitrobenzenesulfonamide (Intermediate 9, 9.88 g, 38.26 mmol) according to the procedure described for Intermediate 10. Desired product was obtained as a pale yellow oil, 18.70 g, 74%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[N:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:12][CH2:23][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:16])[N:22]=2)[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1cccc(CNc2cccc(OCc3ccccc3)c2)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a solution of 3-benzyloxyaniline (0.70 g, 3.51 mmol) in 1,2-dichloroethane (10 ml) were added 6-bromo-pyridine-2-carboxaldehyde (0.65 g, 3.51 mmol), sodium triacetoxyborohydride (1.49 g, 7.03 mmol) and acetic acid (0.80 ml, 14.1 mmol). The reaction mixture was shaken at 40° C. overnight. For work-up dichloromethane (100 ml) and 1 M sodium bicarbonate solution (40 ml) were added and the mixture was shaken. The organic layer was separated, dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (heptane/ethyl acetate=3:1) to yield an orange oil (1.03 g, 80%); MS (ISP): 371.1 ([81Br M+H]+), 369.1 ([79Br M+H]+).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.C(N(CC)CC)C.Cl.[CH2:35]1[CH:39]2[CH2:40][NH:41][CH2:42][CH2:43][N:38]2[C:37](=[O:44])[O:36]1.CN(C)C=O>O>[CH3:26][N:17]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][C:3]([CH2:2][N:41]3[CH2:42][CH2:43][N:38]4[C:37](=[O:44])[O:36][CH2:35][CH:39]4[CH2:40]3)=[CH:4][N:5]=1)=[CH:16]2)[S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:20]
Reactant: O=C1OCC2CNCCN12
Reactant: CN(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(-c3ncc(CN4CCN5C(=O)OCC5C4)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A mixture of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (150 mg), triethylamine (150 μL), hexahydro[1,3]oxazolo[3,4-a]pyrazin-3-one hydrochloride (125 mg) and N,N-dimethylformamide (2 ml) was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (103 mg, yield 56%) as a colorless amorphous form from a fraction eluted with ethyl acetate. MS 530 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:45])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:42]=[CH:41][C:34]([C:35]([O:37][CH2:38][CH2:39]I)=[O:36])=[CH:33][C:32]=2[O:43][CH3:44])=[O:29])[CH:5]=[CH:6][CH:7]=1.[C:46]([O:50][P:51]([O-:58])([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])([CH3:49])([CH3:48])[CH3:47].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:45])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:42]=[CH:41][C:34]([C:35]([O:37][CH2:38][CH2:39][O:58][P:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])([O:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[O:52])=[O:36])=[CH:33][C:32]=2[O:43][CH3:44])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: COc1cc(C(=O)OCCI)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OCCOP(=O)(OC(C)(C)C)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 60 °C
Yield: 54.1 %

Procedure:
To a solution of chiral 2-iodoethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (Example 11, 20 mg, 0.026 mmol) in dimethyl formamide (2 mL) was added potassium di-tert-butylphosphate (Accela ChemBio, 21.8 mg, 0.088 mmol). The reaction mixture was heated at 60° C. for 6 h. The mixture was diluted with ethyl acetate, washed with water and then brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by flash chromatography to give chiral 2-(di-tert-butoxyphosphoryloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (12 mg, 54% yield). MS (ES+) m/z calcd. for C41H50Cl2F2N3O8PNa: [(M+Na)+]: 874. found: 874.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][N:26]=1.CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][C:25]1[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:33])[F:34])=[CH:27][N:26]=1
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cnc(Oc2c(Cl)cc(OCc3ccccc3)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
Then, 0.85 g of 2,6-dichloro-4-benzyloxyphenol, 0.48 g of potassium carbonate, 0.75 g of 2,3-dichloro-5-trifluoromethylpyridine and 10 ml of N,N-dimethylformamide were charged into a reaction vessel, and stirred at 85° to 90° C. for 3 hours. Then, the reaction solution was cooled to room temperature, poured into water and extracted twice with 50 ml of diethyl ether. The ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 1.39 g of 3,5-dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-1-benzyloxybenzene, (yield, 98%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[NH:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16].[OH:18][C:19]([CH3:53])([CH3:52])[CH2:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)=[O:28])[C:23](=[O:45])[N:22]1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O.[Pd]>[CH3:16][N:15]([CH3:17])[CH2:14][CH2:13][NH:12][C:7]1[C:8]2[C:3](=[C:2]([C:33]3[CH:32]=[CH:31][C:30]([NH:29][C:27]([C:24]4[C:23](=[O:45])[N:22]([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)[N:21]([CH2:20][C:19]([OH:18])([CH3:52])[CH3:53])[C:25]=4[CH3:26])=[O:28])=[CH:35][CH:34]=3)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1c(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Reactant: CN(C)CCNc1nccc2c(Br)cccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1c(C(=O)Nc2ccc(-c3cccc4c(NCCN(C)C)nccc34)cc2)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
5-Bromo-N-(2-(dimethylamino)ethyl)isoquinolin-1-amine (0.068 g, 0.2 mmol) was added to a microwave vial equipped with a stirbar, along with 1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-1H-pyrazole-4-carboxamide (0.2 g, 0.3 mmol). Then 1,4-Dioxane (3 ml, 35 mmol) was added into the mixture, followed by 2M K2CO3 (0.5 ml). Then Fibrecat (2.93% Pd, 0.010 g) was added to the mixture. The vial was capped, then placed into CEM Microwave for 10 minutes at 120° C. with 80 Watts of power supplied through Powermax feature. The mixture was diluted with DCM and water, then collected the organic layer by extracting with DCM (3×10 ml). Combined organics, dried over Na2SO4, filtered and concentrated in-vacuo. The crude was purified by ISCO Amino-propyl chromatography using MeOH/DCM as the eluent. This gave the title compounds as a tan amorphous solid (85 mg). MS (ESI pos. ion) m/z: 579 (MH+). Calc'd exact mass for C34H38N6O3: 578.