Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][S:6](=[O:9])(=[O:8])[C:5]2[S:10][C:11]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:12][C:4]=2[NH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C(COC)OC>[O:8]=[S:6]1(=[O:9])[CH2:7][C:2](=[S:26])[NH:3][C:4]2[CH:12]=[C:11]([S:13](=[O:16])(=[O:15])[NH2:14])[S:10][C:5]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CC(=O)N2
Solvent: COCCOC
Product: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CC(=S)N2

Procedure:
A mixture of 2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazine (5 g) and Lawesson's reagent (3.8 g) in dimethoxyethane (25 ml) was heated under reflux for seven hours. The solvent was removed under reduced pressure and the residue was chromatographed over silica gel with chloroform/methanol/acetic acid (90:8:2, v/v/v) as the eluent. The fractions containing the desired product were combined and evaporated to dryness to yield 1.4 g. Two recrystallizations from ethyl acetate/hexane gave pure 2,3-dihydro-4,4-dioxo-6-sulfamoyl-2-thiono-1H-thieno[2,3-b][1,4]thiazine, mp 219°-221° C.
Reaction SMILES: C(=C(O)[C@@H](O)[C@@H](O)C=[O:8])(C)C.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1COCC1>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([OH:8])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CC(C)=C(O)[C@@H](O)[C@@H](O)C=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)O)cc1
Yield: 50 %

Procedure:
For example, alcohol 4 was prepared with a 50-65 percent yield by coupling 2,3,-isopropylidene-D-erythrose with the known Wittig reagent (4-carbethoxybutyl) triphenylphosphonium bromide and KN(SiMe3)2 in THF at -78 degrees C. to 0 degrees C. The alcohol 4 was then treated with p-toluenesulfonyl chloride to furnish the corresponding p-toluenesulfonate. This p-toluenesulfonate was treated with sodium azide NaN3 in dimethyl formamide (DMF) (CH3)2NCHO at about 70 degrees C. to 100 degrees C. to produce the imino ester 6 having the structure ##STR11## wherein R is (C1 -C8) alkyl;
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:19][CH2:18][CH2:17][C:16]2[NH:15][N:14]=[CH:13][C:12]1=2)C1C=CC=CC=1>[Pd]>[NH:15]1[C:16]2[CH2:17][CH2:18][CH2:19][CH:11]([NH2:10])[C:12]=2[CH:13]=[N:14]1
Reactant: O=C(NC1CCCc2[nH]ncc21)OCc1ccccc1
Agent: [Pd]
Product: NC1CCCc2[nH]ncc21
Yield: 96.1 %

Procedure:
Stir a mixture of (4,5,6,7-tetrahydro-1H-indazol-4-yl)-carbamic acid benzyl ester (3.5 g) methanol (50 mL) and palladium on carbon (10%, 0.7 g) on a hydrogenation parr shaker under 50 psi for 3 hours. Remove the reaction from parr shaker and filter the mixture through celite. Concentrate the filtrate to afford 1.7 g of the title compound.
Reaction SMILES: [C:1]1([P:7](Cl)(Cl)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.Cl.[NH2:27][C@H:28]([C:36]([NH:38][C@H:39]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:12]1([CH2:11][O:18][P:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:44]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45])[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:37])[CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NP(=O)(OCc1ccccc1)c1ccccc1)C(=O)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
A mixture of phenylphosphonic dichloride (1.15 ml., 8 mmole) and dry dichloromethane (15 ml.) under argon at 25° is treated dropwise with benzyl alcohol (0.83 ml., 1 eq.) and triethylamine (1.1 ml., 1 eq.) in dichloromethane (5 ml.) over a 20 minute period. A slight exotherm is observed. The reaction mixture is then refluxed for 15 minutes, cooled to 0° (ice bath), and L-phenylalanyl-L-leucine, phenylmethyl ester, hydrochloride salt (1 eq.) is added. The heterogeneous mixture is treated dropwise with triethylamine (2.4 ml., 2.1 eq.) in dichloromethane (8 ml.) over a 5 minute period. The ice bath is removed and the reaction mixture is stirred for an additional 1.5 hours. The solids are removed by filtration and the dichloromethane is stripped from the filtrate. The residue is taken up in ethyl acetate and washed with water, saturated sodium bicarbonate, 5% potassium bisulfate, saturated sodium bicarbonate, brine, dried (MgSO4), and evaporated to a residue. The residue is purified chromatographically to give N-[N-[phenylmethoxy(phenyl)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester.
Reaction SMILES: C([N:8]1[C:15]2[CH:16]=[C:17]([CH2:20][C:21]3[CH:22]=[C:23]([C@H:28]4[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]4)[CH:24]=[CH:25][C:26]=3[Cl:27])[CH:18]=[CH:19][C:14]=2[O:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.Cl>CO.[Pd]>[Cl:27][C:26]1[CH:25]=[CH:24][C:23]([C@H:28]2[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]2)=[CH:22][C:21]=1[CH2:20][C:17]1[CH:18]=[CH:19][C:14]2[O:13][C:10]3([CH2:12][CH2:11]3)[CH2:9][NH:8][C:15]=2[CH:16]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)N(Cc3ccccc3)CC3(CC3)O4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)NCC3(CC3)O4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2 h
Yield: 22.4 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-2-[3-[(4-benzylspiro[3H-1,4-benzoxazine-2,1′-cyclopropane]-6-yl)methyl]-4-chloro-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol (300 mg) in methanol (3 mL), was added ethyl acetate (0.5 mL), 10% palladium on charcoal (40 mg), and 0.3 mL conc. HCl. The reaction mixture was stirred under hydrogen balloon pressure for 2 h then filtered through a celite bed which was washed with methanol, and the resulting filtrate was concentrated to a residue which was purified by preparative HPLC to furnish (2S,3R,4R,5S,6R)-2-[4-chloro-3-(spiro[3,4-dihydro-1,4-benzoxazine-2,1′-cyclopropane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol (56 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([O:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[CH:7][C:6](=[O:23])[N:5]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[N:4]=1.[ClH:34].O1CCOCC1.CCOCC>C(Cl)Cl>[ClH:34].[OH:1][CH2:2][C:3]1[C:8]([O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:7][C:6](=[O:23])[N:5]([C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)cc3)nc2CO)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(-n2nc(CO)c(OC3CCNCC3)cc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirring solution of tert-butyl 4-(3-(hydroxymethyl)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (200 mg, 0.417 mmol) in DCM (3 mL) at room temperature under argon was added 4 M HCl in dioxane (0.521 mL, 2.085 mmol). The reaction mixture was stirred at room temperature overnight. Et2O (10 mL) was added to the reaction mixture. The solid product was collected by filtration and further washed with ether (2 mL×2). After drying under vacuum for 2 hours, 171 mg (100%) of 6-(hydroxymethyl)-2-(4-(methylsulfonyl)phenyl)-5-(piperidin-4-yloxy)pyridazin-3(2H)-one HCl salt was obtained as an off-white solid. MS (ESI) 380 (M+H).
Reaction SMILES: [C:1](=[O:18])(SCC)[O:2][O:3][CH:4]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]([CH3:7])[CH3:6].S(Cl)([Cl:22])(=O)=O>C(Cl)Cl>[Cl:22][C:1]([O:2][O:3][CH:4]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]([CH3:7])[CH3:6])=[O:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCSC(=O)OOC(OC(=O)C(C)(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(OOC(=O)Cl)OC(=O)C(C)(C)C

Procedure:
A solution of (45) (4.76 mmol) in CH2Cl2 at 0° C. was treated with sulfuryl chloride (1.1 mmol) under N2 for 10 min, then the reaction mixture was concentrated to dryness in vacuo to afford the crude chloroformate (46) in quantitative yield, which used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.00 (d, 6H), 1.20 (d, 9H), 2.143 (m, 1H), 6.54 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].O1CCCC1.[C:16](Cl)(=[O:36])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:16](=[O:36])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCCC(=O)Nc1ccc([N+](=O)[O-])cc1
Yield: 82.1 %

Procedure:
In a three necked flask equipped with a dropping funnel, a thermometer and a reflux condenser, 138 g of p-nitroaniline was dissolved in a mixed solvent consisting of 3000 ml of tetrahydrofuran and 140 ml of pyridine while passing nitrogen gas through the flask. Then, 364 g of eicosanoylchloride placed in the dropping funnel was gradually dropped into the flask over a time span of 20 minutes, while stirring the reaction mixture. After the completion of the dropping, the reaction mixture was further stirred for 2 hours. A solid reaction product was produced. The solid reaction product was collected by filtering, the filtrate was concentrated under a reduced pressure to produce crystals. The crystals were collected and recrystallized from ethyl alcohol. As a result, 355 g of 4'-nitro-n-eicosane anilide was obtained at a yield of 82%.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([C:38]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Br:1])[C:3]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=6)[CH2:14][CH2:13]5)=[C:4]4[N:9]=3)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: Brc1cnc2[nH]c(-c3ccc(Cn4cccn4)cc3)nc2c1N1CCN(Cc2ccncc2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-pyridin-4-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.039 g, 0.10 mmol) and EtOH (3.5 ml) was added 4-pyrazol-1-ylmethyl-benzaldehyde (0.024 g, 0.13 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.40 ml, 0.40 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (2 to 5%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.025 g, 48%); 1H-NMR (500 MHz, DMSO-d6) 2.63 (br s, 4H, piperazine N(CH2)2), 3.61 (s, 2H, NCH2pyridyl), 3.69 (br s, 4H, piperazine N(CH2)2), 5.42 (s, 2H, C6H4CH2N), 6.30 (t, J=2.0 Hz, 1H, pyrazole 4-H), 7.35 (d, J=8.3 Hz, 2H) and 8.14 (d, J=8.2 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 7.39 (d, J=5.9 Hz, 2H, pyridine 3-H, 5-H), 7.49 (d, J=1.7 Hz, 1H, pyrazole-H), 7.86 (d, J=2.2 Hz, 1H, pyrazole-H), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.54 (d, J=5.9 Hz, 2H, pyridine 2-H, 6-H), 13.50 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29](Br)[CH:30]=[CH2:31]>>[CH2:31]([O:28][CH:16]1[CH:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17]1)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(O)C1
Product: C=CCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCc2ccccc2)cc1

Procedure:
Analogously to Method D, 12 g of tert-butyl 4-(4-benzyloxyphenyl)-3-hydroxypiperidine-1-carboxylate and 5.4 ml of allyl bromide are reacted. The title compound is obtained as a yellowish oil. Rf=0.31 (1:3 EtOAc-heptane); Rt=5.80.
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27]([F:35])[CH:26]=1)[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)C1C=CC=CC=1>[Pd].CCO>[NH2:11][C@@H:12]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:32])[F:34])=[C:27]([F:35])[CH:26]=1)[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(F)(F)F)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](N)c1ccc(C(F)(F)F)c(F)c1
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a solution of 61 (1.04 g, 2.09 mmol) and EtOH (25 mL), was added Pd/C (10% Degussa wet, 0.5 g). The mixture was hydrogenated overnight under balloon pressure. The mixture was then filtered and evaporated to afford 0.52 g (68.5%) of 63 as thick oil.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:25])[C@@H:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2.[Br:26][CH2:27][C:28]([C:30]1[N:31]=[C:32]([CH3:35])[S:33][CH:34]=1)=[O:29].CC(O)C>C(#N)C>[Br-:26].[CH3:35][C:32]1[S:33][CH:34]=[C:30]([C:28](=[O:29])[CH2:27][N+:1]23[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]2)[C@@H:3]([O:9][C:10](=[O:25])[C@@H:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:2]3)[N:31]=1
Reactant: Cc1nc(C(=O)CBr)cs1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CC(C)O
Product: Cc1nc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cs1
Product: [Br-]
Yield: 35.4 %

Procedure:
(R)-Phenyl-phenylamino-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Diastereoisomer 1 of C2) (75.0 mg, 0.22 mmol) and 2-bromo-1-(2-methylthiazol-4-yl)ethanone (I228) (49.1 mg, 0.22 mmol) in acetonitrile (5 mL) is heated at 100° C. for 75 minutes under microwave irradiation (UPLC-MS monitoring: complete conversion). The solvent is removed and the resulting brown solid is tritured with iPr2O/Et2O (1/1) and then with iPrOH to obtain the title compound as a grey powder (43.3 mg, 35% yield, bromide salt, single diastereoisomers).
Reaction SMILES: C1COCC1.Cl[C:7]1[NH:11][C:10]2[CH:12]=[C:13]([NH:27][C:28]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:37])=[O:29])[CH:14]=[C:15]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[CH3:26])=[O:17])[C:9]=2[N:8]=1.[CH:38]([O:41][CH2:42][CH2:43][NH2:44])([CH3:40])[CH3:39]>C(OCC)(=O)C>[Cl:37][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([F:36])[C:30]=1[C:28]([NH:27][C:13]1[CH:14]=[C:15]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=2[CH3:26])=[O:17])[C:9]2[N:8]=[C:7]([NH:44][CH2:43][CH2:42][O:41][CH:38]([CH3:40])[CH3:39])[NH:11][C:10]=2[CH:12]=1)=[O:29]
Reactant: CC(C)OCCN
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2c(F)cccc2Cl)cc2[nH]c(Cl)nc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2c(F)cccc2Cl)cc2[nH]c(NCCOC(C)C)nc12
Yield: 72.2 %

Procedure:
THF (1 mL) was added to 2-chloro-6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-1H-benzimidazole-4-carboxamide (50 mg) and 2-aminoethyl isopropyl ether (32 mg). The mixture was stirred at 150° C. in a sealed pressure-proof stainless steel container for 17 hours. The reaction mixture was diluted with ethyl acetate and washed with brine and concentrated under reduced pressure. The residue was purified on column chromatography to obtain 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[2-(propan-2-yloxy)ethyl]amino}-1H-benzimidazole-4-carboxamide (41 mg) as pale yellow powder. This was dissolved in MeOH (1 mL), 2N hydrogen chloride/EtOH solution (1 Eq) was added, and it was stirred and concentrated. The residue was triturated in diethyl ether, and the precipitate was collected by filtration and dried to obtain the titled compound (35 mg) as white powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.ClC1C=C(NC2C3C(=CC=C(C4OC(CNCC[S:72](C)(=[O:74])=[O:73])=CC=4)C=3)N=CN=2)C=CC=1OCC1C=CC=C(F)C=1.[OH-:76].[Na+]>C1COCC1>[S:72]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)([OH:74])(=[O:76])=[O:73].[Cl:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: [OH-]
Reactant: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: Cl
Agent: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 2 liter, 3 neck round bottom flask equipped with a mechanical stirrer was charged with 74.95 grams of the HCl salt of 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde (prepared according to the Procedure D and Examples 1 (a)-(g), and 749.5 mL THF. To this slurry was charged 84.45 mL of 2M NaOH and the reactants were stirred for 30 minutes. The layers were separated and then the organic layer was washed with 160 mL of H2O. The organic layer was slurried with 3.75 grams of Darco G60 and filtered through celite. The filtrate was collected and slowly added to 33.54 grams of toluenesulfonic acid monohydrate with rapid stirring. The solids slowly precipitated out at ambient temperature. The mixture was cooled to 0° C. and stirred for 10 minutes. The mixture was filtered and pulled dry with a rubber dam, then dried in vacuo at 50° C. overnight. The yield of 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde tosylate was 84.25 grams (88.8%).
Reaction SMILES: [CH3:1][C:2]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)([CH3:8])[C:3]([O:5]CC)=[O:4].O[Li].O.Cl>C1COCC1.O>[CH3:8][C:2]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 50 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Ethyl 2-methyl-2-(5-nitro-1H-indol-2-yl)propanoate (4.60 g, 16.7 mmol) was dissolved in THF/water (2:1, 30 mL). LiOH.H2O (1.40 g, 33.3 mmol) was added and the mixture was stirred at 50° C. for 3 h. The mixture was made acidic by the careful addition of 3N HCl, The product was extracted with ethylacetate and the combined organic phases were washed with brine and dried over magnesium sulfate to give 2-methyl-2-(5-nitro-1H-indol-2-yl)propanoic acid (4.15 g, 99%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][CH:6]=2.[CH3:14][S:15]SC>C1COCC1>[CH3:13][O:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([S:15][CH3:14])[CH:3]=[N:4]2
Reactant: COc1cccc2ncc(Br)cc12
Reactant: CSSC
Solvent: C1CCOC1
Product: COc1cccc2ncc(SC)cc12
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-bromo-5-methoxy quinoline (2.37 g, 10 mmol) prepared in stage B of example 10 in THF (25 mL) was added 2.5M n-buLi (4 mL, 10 mmol) at −78° C. The solution is stirred at −78° C. for 45 min and dimethyl disulfide (1.8 g, 20 mmol) is added. The resultant solution is stirred for 3 hours and then quenched with saturated NH4Cl (30 mL). Extraction with dichloromethane, drying, filtering and evaporation in vacuo afford the title compound
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:18][CH2:19][C@H:20]([S:22][CH2:23][C@@:24]([CH3:29])([C:26]([OH:28])=[O:27])[NH2:25])[CH3:21])=O)C1C=CC=CC=1.[ClH:30]>>[ClH:30].[NH2:18][CH2:19][C@H:20]([S:22][CH2:23][C@@:24]([CH3:29])([C:26]([OH:28])=[O:27])[NH2:25])[CH3:21]
Reactant: C[C@H](CNC(=O)OCc1ccccc1)SC[C@](C)(N)C(=O)O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CN)SC[C@](C)(N)C(=O)O
Temperature: 25 °C

Procedure:
The product of Example-3C, S-[(1R)-2-(Benzyloxycarbonylamino)-1-methylethyl]-2-methyl-L-cysteine trifluoroacetate, (0.5 g, 1.14 mmol) was dissolved in 6N HCl and refluxed for 1.5 hour. The mixture was then cooled to room temperature and extracted with EtOAc. The aqueous layer was concentrated in vacuo to give the title product, (2R,5R)-S-(1-amino-2-propyl)-2-methyl-cysteine hydrochloride (0.29 g), which was used without further purification. 1H NMR (H2O, 400 MHz) δ1.2 (m, 3H), 1.4 (m, 3H), 2.7 (m, 1H), 2.8-3.2 (m, 2H), 3.4 (m, 1H). (some doubling of peaks due to rotameric forms). MS m/z (electrospray): 193 [M+H+] (61%), 176 (53), 142 (34), 134 (100), and 102 (10).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([CH3:13])[CH:5]=1.C[O:16]C(OC)N(C)C.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([CH:13]=[O:16])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C)c1
Reactant: COC(OC)N(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-methyl-4-nitro-benzoic acid methyl ester (24.99 g, 128.1 mmol) and N,N-dimethylformamide dimethyl acetal (40.0 mL, 300 mmol) was heated at 140° C. for 22.5 h. After cooling to rt, the reaction mixture was concentrated and the residue was crystallized from MeOH to give a purple solid. This solid was dissolved in THF (500 mL) and water (500 mL), and sodium periodate (62.62 g, 292.8 mmol) was added followed by additional sodium periodate (15.6 g, 72.9 mmol) two hours later. After stirring at rt for an additional 1 h, the reaction mixture was filtered through Celite washing with EtOAc (2 L). The filtrate was washed with saturated NaHCO3 (600 mL) and the organic layer was dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was passed through a pad of silica gel, washing with CH2Cl2/hexanes (75%-100%). The filtrate was concentrated and dried to give 3-formyl-4-nitro-benzoic acid methyl ester as yellowish solid. MS (EI): cal'd 210.0 (MH+), exp 210.2 (MH+).