Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[C:42]([CH2:49][O:50][Si:51]([CH:58]([CH3:60])[CH3:59])([CH:55]([CH3:57])[CH3:56])[CH:52]([CH3:54])[CH3:53])=[N:43][N:44]([CH2:46][CH2:47][OH:48])[CH:45]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:70][S:71](Cl)(=[O:73])=[O:72]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[C:42]([CH2:49][O:50][Si:51]([CH:55]([CH3:57])[CH3:56])([CH:58]([CH3:60])[CH3:59])[CH:52]([CH3:53])[CH3:54])=[N:43][N:44]([CH2:46][CH2:47][O:48][S:71]([CH3:70])(=[O:73])=[O:72])[CH:45]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[Si](OCc1nn(CCO)cc1-n1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC[C@@H]4C)n3c2)c2ccccc21)(C(C)C)C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OCc1nn(CCOS(C)(=O)=O)cc1-n1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC[C@@H]4C)n3c2)c2ccccc21)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
A solution of Intermediate 74i (134 mg, 0.16 mmol) in DCM (1.6 mL) was treated with DIPEA (83 μL, 0.48 mmol) then cooled to 0° C. Methanesulfonyl chloride was added and the mixture was stirred at 0° C. for 5 min then at RT for 1 h. The mixture was diluted with DCM and a saturated aqueous sodium bicarbonate solution and the phases were separated. The aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-8% MeOH in DCM, to give the title compound (107 mg, 73%). LCMS (Method 3): Rt 5.06 min, m/z 917.4 [MH+].
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24]([OH:26])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@@H:36]([NH2:39])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@@H:36]([NH:39][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([F:14])[C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][CH:22]=2)=[O:26])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)cc1F
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A80) and (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)(=O)=O.[C-:14]#[N:15].[K+].C(=O)(O)[O-].[Na+]>CCO.O>[Cl:13][C:11]1[CH:10]=[N:9][CH:8]=[C:7]([CH2:6][N+:15]#[C-:14])[CH:12]=1
Reactant: CS(=O)(=O)OCc1cncc(Cl)c1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [C-]#[N+]Cc1cncc(Cl)c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
To a mixture of (5-chloropyridin-3-yl)methyl methanesulfonate (2.09 g, crude) in EtOH (45 mL) and water (5 mL) was added potassium cyanide (926 mg, 14.3 mmol), and the resulting mixture was stirred at 85° C. for 2 h. Sodium bicarbonate was added and the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (50% ethyl acetate in petroleum ether) to afford the title compound as a yellow solid (820 mg, 5.43 mmol, 48% yield, 2 steps). MS (ESI) m/z 153.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:3]1C(O)=O.[OH-].[Na+].[Na].[F-:15].[Na+]>O>[Cl:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:3]1[F:15]
Reactant: [F-]
Reactant: COC(=O)C1(Cl)CC1C(=O)O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: COC(=O)C1(Cl)CC1F
Yield: 79.1 %

Procedure:
To 111 g of 2-chloro-2-methoxycarbonyl-1-cyclopropanecarboxylic acid was added 200 ml of water. Further, a solution of 24.87 g of sodium hydroxide dissolved in 300 ml of water was added thereto under ice-cooling and stirring to thereby give sodium salt. To this aqueous solution was added 52.25 g of sodium fluoride. Next, 1.3 equivalents, to carboxylic acid, of 10% (v/v) fluorine gas (diluted with nitrogen: 600 ml/min) was bubbled into this solution under ice-cooling and stirring. After the completion of the bubbling, the pH value of the reaction mixture was regulated to 8 to 9 by adding a 1N aqueous solution of sodium hydroxide. Then it was extracted with two 250 ml portions of dichloromethane. The organic layer was collected and dried over sodium sulfate. After evaporating the solvent under reduced pressure, 75 g of the title compound was obtained in the form of a crude product (cis:trans=3:2). After adjusting pH value of the separated aqueous layer to 2 to 3 with hydrochloric acid, it was extracted with two 100 ml portions of dichloromethane. Thus 23.1 g of the starting compound was recovered. After distilling the crude reaction product, the total yield of the cis- and trans-compounds was 76.4% (calculated by excluding the recovered starting compound). The analytical data of the title compound are as follows.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24](=[O:38])[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)[CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1.[CH3:39][N:40]=[C:41]=[O:42]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24](=[O:38])[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]2)[CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[C:41]([NH:40][CH3:39])=[O:42])=[CH:2]1
Reactant: CN=C=O
Reactant: COc1ccccc1CNCC(Cc1c[nH]c2ccccc12)NC(=O)CN1CCN(c2ccccc2)CC1
Solvent: C1CCOC1
Product: CNC(=O)N(Cc1ccccc1OC)CC(Cc1c[nH]c2ccccc12)NC(=O)CN1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a room temperature solution of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane (0.40 g, 0.78 mmole) in 10 ml of anhydrous tetrahydrofuran was added dropwise methyl isocyanate (140μl, 2.3 mmoles). The resulting mixture was then stirred for 16 hours at room temperature. The tetrahydrofuran was removed in vacuo. The title product was isolated by consecutive washes with ethyl acetate, water, and brine, and then dried over sodium sulfate. Flash chromatography using silica gel and a methanol/methylene chloride (5/95) eluant provided 396 mg of the homogeneous product as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([CH:13]2[CH2:15][CH2:14]2)O)=[CH:5][CH:4]=1)#[N:2].[Br-].[Li+].N1C(C)=CC(C)=CC=1C.P(Br)(Br)[Br:28]>CCOCC.O>[Br:28][CH2:15][CH2:14][CH:13]=[CH:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(CCC(O)C2CC2)cc1
Reactant: BrP(Br)Br
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: Cc1cc(C)nc(C)c1
Product: N#Cc1ccc(CCC=CCCBr)cc1
Temperature: -60 °C
Reaction time: 2 h
Yield: 130.7 %

Procedure:
To a solution of 9.8 g of 4-cyanophenylethyl cyclopropyl carbinol in 140 ml of ether was added 4.24 g of lithium bromide and 3 ml of 2,4,6-collidine. The mixture was cooled to -60° C. and 9.8 g of phosphorus tribromide was added over a five minute period. The reaction mixture was allowed to warm to 0° C., kept at that temperature for two hours and then allowed to warm to 18° C. Collidine (18 ml) was added, and after 15 minutes of stirring, the mixture was poured into 200 ml of water and 100 ml of ether. The ether extracts were washed with dilute aqueous sulfuric acid and water, dried over anhydrous magnesium sulfate and concentrated to a volume of 150 ml. Zinc bromide (11.6 g) was then added with cooling, and the mixture was stirred at room temperature for 29 hours. The ether solution was washed with water, dried and concentrated to give 12.5 g of 4-(6-bromohex-3-enyl)benzonitrile as a yellow oil.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1>C(O)C>[Cl:23][C:19]1[CH:18]=[C:17]2[C:22]([C:13]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([S:1]([OH:11])(=[O:10])=[O:2])=[CH:8][CH:7]=3)=[N:14][CH:15]=[N:16]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Solvent: CCO
Product: O=S(=O)(O)c1ccc(Nc2ncnc3cc(Cl)ccc23)cc1

Procedure:
Sulphanilic acid (12.1 g, 0.07 mole) was partly dissolved in 280 milliliters of aqueous ethanol (50% by volume) at reflux and 4,7-dichloroquinazoline (13.9 g, 0.07 mole) was added rapidly in a few portions. The mixture was refluxed for a further 15 minutes, cooled and filtered to give the title compound hemihydrate of melting point greater than 300° C.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]([CH2:40][CH3:41])[CH2:37][CH2:38][OH:39]>>[CH2:40]([N:36]([CH2:37][CH2:38][OH:39])[CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29])[CH3:41]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: CCN(CCO)CCCCN
Product: CCN(CCO)CCCCNC(=O)Nc1snc(OCc2c(F)cc(C)c(F)c2F)c1C(N)=O

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-[(4-amino-butyl)-ethyl-amino]-ethanol by the procedure analogous to Example 1. MS (APCl, m/z): 504 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([NH:10]C(=O)OC(C)(C)C)=[CH:9][C:2]=12>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([NH2:10])=[CH:9][C:2]=12
Reactant: CC(C)(C)OC(=O)Nc1cc2nccnc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc2nccnc2s1
Yield: 80.6 %

Procedure:
A red solution of tert-butyl thieno[2,3-b]pyrazin-6-ylcarbamate (5.09 mmol, 1.28 g) in 66% TFA in CH2Cl2 25 mL was stirred overnight at room temperature The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate, washed with NaHCO3 solution, brine, dried and evaporated to give thieno[2,3-b]pyrazin-6-amine 106 (620 mg, 81%). NMR (400 MHz, DMSO-d6) 5.98 (s, 1H), 7.17 (br s, 2H), 7.93 (d, J=2.7 Hz, 1H), 8.20 (d, J=2.7 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[C:13]1([S:19]([C:22]2[CH:27]=[CH:26][C:25](F)=[C:24]([F:29])[CH:23]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([O:8][C:25]2[CH:26]=[CH:27][C:22]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])=[CH:23][C:24]=2[F:29])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(Br)c1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(F)c1
Product: O=C(O)Cc1cc(Br)cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 55 step (v) and the product from example 24 step (i).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])(O)[CH3:13])[C:6]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](\[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])/[CH3:13])[C:6]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccc(Cl)cc2Cl)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: C/C(=C/n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(Cl)cc1Cl
Temperature: 0 °C

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(2,4-dichlorophenyl)propan-2-ol (1 g, 2.36 mmol, 1 equiv.) was refluxed with 25% sulfuric acid (7 mL) for 2 h. The reaction mixture was cooled to 5° C. in ice-water bath. KOH (15% aqueous solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water (10 mL) followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by silica gel chromatography (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of isomers, which were separated by HPLC. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.30 (m, 2H), 7.18 (d, 1H), 7.15 (d, 1H), 7.0 (d, 1H), 6.80 (d, 1H), 6.70 (s, 1H), 4.70 (m, 1H), 4.05 (m, 1H), 3.80 (m, 1H), 3.30 (m, 1H), 3.05 (m, 1H), 2.98 (s, 3H), 2.90 (m, 1H), 2.30 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:54])[N:5]1[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[O:39][CH3:40])=[N:14][C:13]3[N:41]([S:44]([C:47]4[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=4)(=[O:46])=[O:45])[CH:42]=[CH:43][C:12]=3[C:6]1=[N:7]2.[NH4+:55].[OH-]>O1CCCC1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:7][C:6]2[C:12]3[CH:43]=[CH:42][N:41]([S:44]([C:47]4[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=4)(=[O:45])=[O:46])[C:13]=3[N:14]=[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:30][CH2:31][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:33][CH2:34]5)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[O:39][CH3:40])[N:5]=2)[C:3]=1[C:4]([NH2:55])=[O:54]
Reactant: [NH4+]
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c2nc3cccc(F)c3c(=O)n12
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nc(Nc2cccc(F)c2C(N)=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2n1
Yield: 60.4 %

Procedure:
A solution of 8-fluoro-5-[(2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (4.5 g, 5.81 mmol) and 30% aqueous NH4OH (75 mL, 5.81 mmol) and tetrahydrofuran (75 mL) was stirred at rt overnight in a 200 mL rb flask. The solution was extracted with ethyl acetate (250 mL) and brine (50 mL). The organic layers were dried over MgSO4, filtered, concentrated onto Celite and purified on SiO2 (1-10% MeOH in CH2Cl2 and 0.1% NH4OH) to afford 2-fluoro-6-({2-[(2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (2.78 g, 3.51 mmol, 60% yield) as a mixture with several other products. The desired product was the predominant component. The product weight was 2.78 grams. ESIMS (M+H)+=792.42 (100%). This material was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH:13]=[C:14]([N:19]=[N+]=[N-])[C:15]([O:17][CH3:18])=[O:16].[CH3:22]C(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.IC>C1C=CC=CC=1.O>[CH3:22][N:19]1[C:5]2[C:4](=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[CH:13]=[C:14]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C(=Cc1ccc(OC)c(OC)c1OC)N=[N+]=[N-]
Reactant: CC(C)(C)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Solvent: CI
Product: COC(=O)c1cc2c(OC)c(OC)c(OC)cc2n1C
Reaction time: 0.25 h

Procedure:
Methyl 3-(2,3,4-trimethoxyphenyl)-2-azidopropenoate (799 mg), potassium tert-butoxide (438 mg) and 18-crown-6 (71 mg) were dissolved in dry benzene (60 mL), and the solution was stirred for 15 minutes. Iodomethane (0.28 mL) was then added, and the mixture was stirred overnight. Water was added to the reaction mixture to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.CCN(CC)CC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[N+:47]([C:50]1[CH:51]=[C:52](B(O)O)[CH:53]=[CH:54][CH:55]=1)([O-:49])=[O:48]>CN(C)C=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:47]([C:50]1[CH:55]=[C:54]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)[CH:53]=[CH:52][CH:51]=1)([O-:49])=[O:48]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2cccc(-c3cccc([N+](=O)[O-])c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (35 mg, 0.104 mmol) (Starting Material 1), Et3N (58 μL, 0.415 mmol), tri-o-tolylphosphine (6 mg, 0.020 mmol) (Aldrich), Pd(OAc)2 (2 mg, 0.009 mmol) (Aldrich), and 3-nitrophenylboronic acid (26 mg, 0.156 mmol) (Aldrich) in 3 mL of dry N,N-dimethylformamide was heated at 100° C. for 16 h. The reaction mixture was allowed to cool to room temperature, concentrated in vacuo to remove N,N-dimethylformamide, and then directly purified by flash chromatography (Merck Silica gel 60, 70-230 mesh, 10% ethyl acetate-hexanes then 25% ethyl acetate-hexanes elution) to provide pure (Z)-1,3-dihydro-4-(3-nitrophenyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (24.1 mg, 70%) as an orange solid (mp 197-199° C.).
Reaction SMILES: [NH2:1][C:2]1([CH3:23])[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH2:13][CH2:14][C:15]=4[CH:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:31](=O)(O)[O-:32].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N:1]([C:2]1([CH3:23])[CH2:3][CH2:4][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH2:13][CH2:14][C:15]=4[CH:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:6][CH2:7]1)=[C:31]=[O:32]
Reactant: CC1(N)CCN(C[C@@H]2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Reactant: O=C([O-])O
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(N=C=O)CCN(C[C@@H]2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Yield: 40 %

Procedure:
A solution of (1R)-1-[(4-amino-4-methyl-1-piperidinyl)methyl]-1,2,5,6-tetrahydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (1.294 g, 4.09 mmol) in DCM (30 ml) under argon at rt was treated with triethylamine (0.684 ml, 4.91 mmol), then di-tent-butyl dicarbonate (1.045 ml, 4.50 mmol) and finally 4-dimethylaminopyridine (0.050 g, 0.409 mmol) and stirred at rt for 1 h. The reaction mixture was treated with aq sodium bicarbonate (100 ml) and extracted with DCM (3×200 ml). The combined organic fractions were dried (MgSO4), filtered and evaporated to give the crude product as a yellow solid which was then chromatographed (0-10% methanol/DCM, Rf=0.5 in 10% methanol/DCM) to give the product as a white solid (561 mg, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([OH:8])=O.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH2:43][CH2:44][CH:45]([C:47]1[CH:52]=[C:51](OC)[C:50](OC)=[C:49](OC)[CH:48]=1)[OH:46]>ClCCl>[OH:46][CH:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:44][NH:43][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(OC)cc(C(=O)O)c1
Reactant: COc1cc(C(O)CN)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(OC)cc(C(=O)NCC(O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
A suspension of 3,5-dimethoxybenzoic acid (1.00 g, 5.49 mmol) in dichloromethane (50 mL) at 0° C. was treated with HOBt hydrate (0.742 g, 5.49 mmol), stirred for 15 minutes, treated with EDCI (1.05 g, 5.49 mmol) in one portion, stirred for an additional 25 minutes, treated with triethylamine (1.84 g; 2.53 mL, 1.9 mmol) and the acetate salt of 2-amino-1-(3,4,5-trimethoxyphenyl)ethanol (1.58 g, 005.49 mmol), stirred for 18 hours while warming to room temperature, and concentrated. The concentrate was partitioned between ethyl acetate (400 mL) and water (200 mL), and the organic extract was washed sequentially with 10% KHSO4 (200 mL), water (100 mL), NaHCO3 (200 mL), and water (100 mL), dried (MgSO4), filtered, and concentrated to provide 1.56 g of the desired product as a white foamy semi-solid.
Reaction SMILES: CC([NH:9][S:10](/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)(=[O:12])=[O:11])(C)CC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15](/[CH:14]=[CH:13]/[S:10]([NH2:9])(=[O:11])=[O:12])=[CH:20][CH:19]=1
Reactant: CC(C)(C)CC(C)(C)NS(=O)(=O)/C=C/c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)/C=C/c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
To (E)-2-(4-chloro-phenyl)-ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (5.0 g, 15.2 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (10 ml) and the mixture was stirred for 15 min. The mixture was concentrated in vacuo to afford a solid. The solid was washed with dichloromethane (5 ml) and heptane (150 ml). The resultant solid was collected by suction filtration. The solid was dried under vacuum at room temperature to afford (E)-2-(4-chloro-phenyl)-ethenesulfonic acid amide (2.95 g, 89%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]([N+:14]([O-])=O)=[C:11]([NH2:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CO.[Pd]>[O:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:12]=[C:11]([NH2:13])[C:10]([NH2:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5]1
Reactant: Nc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 108.3 %

Procedure:
0.1 g of 10% Pd/C was added to 1.0 g of 5-morpholin-4-yl-2-nitro-phenylamine (4.3 mmol) dissolved in 43 mL of methanol, and allowed to stir under hydrogen balloon at room temperature for 4 hours. The mixture was filtered with diatomaceous earth to remove the catalyst, and concentrated under reduced pressure to obtain 0.9 g of 4-morpholinobenzene-1,2-diamine (yield 100%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:15][C:11]1[CH:10]=[C:9]([C:3]([OH:8])([C:2]([F:1])([F:18])[F:19])[C:4]([F:5])([F:6])[F:7])[CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a solution of 1,1,1,3,3,3-hexafluoro-2-(3-nitrophenyl)propan-2-ol (6.0 g, 21 mmol) in ethanol (60 mL) was added ammonium formate (6.0 g) and Pd/C (10%, 600 mg). The mixture was heated at reflux for 5 min and was cooled to room temperature. The Pd catalyst was removed via filtration through Celite using ethanol. The combined filtrate was evaporated to dryness and the residue was washed with CH2Cl2 to yield 2-(3-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4.1 g, 67% over two steps). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.11 (t, J=7.9 Hz, 1H), 6.93 (s, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.65 (dd, J=8.0, 1.6 Hz, 1H), 5.34 (s, 2H). MS (ESI) m/e (M+H+) 260.1.