Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[CH2:5][NH:6][NH2:7].C([O:17][C:18](=O)[CH:19]=[C:20]([NH2:24])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:24][C:20]1[NH:7][N:6]([CH2:5][C:4]2[CH:8]=[CH:9][C:10]([C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:3]=2)[C:18](=[O:17])[CH:19]=1
Reactant: NNCc1ccc(C(F)(F)F)c(Cl)c1
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(C(F)(F)F)c(Cl)c2)[nH]1
Reaction time: 8 h

Procedure:
33 g of 3-chloro-4-trifluoromethylbenzylhydrazine were added dropwise, under nitrogen, to a solution of 23.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and a pinch of p-toluenesulphonic acid in 100 ml of ethanol. After stirring overnight, the product which had precipitated was filtered off and recrystallised from ethanol. Melting point: 83°, 24 g (56%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=O)[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([CH3:30])[CH:20]=1)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[C:21]([CH3:30])[CH:20]=3)[CH3:18])=[O:14])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15]
Reactant: Cc1cc(C(C)N)ccc1C(C)(C)C#N
Reactant: O=C(O)Cn1cnc2ccc(F)c(Cl)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(C(C)NC(=O)Cn2cnc3ccc(F)c(Cl)c32)ccc1C(C)(C)C#N
Yield: 159.6 %

Procedure:
To a solution of (7-chloro-6-fluoro-1H-benzimidazol-1-yl)acetic acid (100 mg, 0.44 mmol) prepared according to scheme 12, 2-{4-[1-aminoethyl]-2-methylphenyl}-2-methylpropanenitrile (88.5 mg 0.44 mmol) prepared according to scheme 16 and DMAP (106 mg, 0.88 mmol) stirred in anhydrous DMF (2.0 mL) is added HATU (166 mg, 0.44 mmol) after 18 hours of stirring, the mixture is diluted with methanol (200 μL) the solution is purified directly on a preparative LCMS system equipped with a Synergi Polar (4 u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product (+) and (−)-2-(7-chloro-6-fluoro-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-methylphenyl]ethyl}acetamide (290 mg, 53%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.48 (d, J=7.03 Hz, 3H) 1.76 (s, 6H) 2.61 (s, 3H) 4.99 (q, J=7.03 Hz, 1H) 5.19-5.36 (m, 2H) 7.13-7.25 (m, 3H) 7.33 (d, J=8.20 Hz, 1H) 7.59 (dd, J=8.98, 4.30 Hz, 1H) 8.14 (s, 1H), MS [M+H], calcd: 413.2, found: 413.3.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]2[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:44]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[N:3]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]2[CH2:15][Br:44]
Reactant: C[Si](C)(C)CCOCn1nc2c(CO)cc(C(F)(F)F)cc2c1Br
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc2c(CBr)cc(C(F)(F)F)cc2c1Br
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(3-Bromo-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methanol (198 mg, 0.48 mmol) and triphenylphosphine (253 mg, 0.96 mmol) were combined in tetrahydrofuran (3 mL) and cooled to 0° C. N-Bromosuccinimide (180 mg, 1.01 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (5% ethyl acetate/hexanes) gave 140 mg (61%) as a light brown oil. 1H-NMR (CDCl3, 300 MHz) δ 7.90 (s, 1H), 7.64 (s, 1H), 5.94 (s, 2H), 4.95 (s, 2H), 3.51-3.57 (m, 2H), 0.82-0.87 (m, 2H), 0.08 (s, 9H).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].I[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1.[OH:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1>O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:19]1[C:14]([C:41]2[CH:42]=[C:37]([OH:36])[CH:38]=[CH:39][CH:40]=2)=[N:15][C:16]([CH3:35])=[CH:17][CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(O)c3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 3-hydroxyphenylboronic acid (81 mg) under an argon atmosphere, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (6.8 mg, yield 15%).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][NH:5][C:6](=[O:21])[C@H:7]([CH3:20])[CH2:8][C@H:9]([OH:19])[C@@H:10]([NH2:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[O:33]=[C:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([N:48]2[CH2:52][CH2:51][CH2:50][C:49]2=[O:53])[CH:47]=1)[C:42](O)=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:11]([C@H:10]([NH:18][C:42](=[O:43])[C:41]1[CH:40]=[C:39]([N:35]2[CH2:36][CH2:37][CH2:38][C:34]2=[O:33])[CH:47]=[C:46]([N:48]2[CH2:52][CH2:51][CH2:50][C:49]2=[O:53])[CH:45]=1)[C@@H:9]([OH:19])[CH2:8][C@H:7]([C:6](=[O:21])[NH:5][CH2:4][CH2:3][C:2]([CH3:22])([CH3:1])[CH3:23])[CH3:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NCCC(C)(C)C
Reactant: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.2 %

Procedure:
To a solution of (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (3,3-dimethylbutyl)amide (D2) (46 mg, 0.145 mmol) in DMF (2 ml) was added iPr2NEt (61 μl, 0.348 mmol) followed by 3,5-bis-2-oxopyrrolidin-1-yl)benzoic acid (D8) (50 mg, 0.174 mmol) and HATU (77 mg, 0.203 mmol). The reaction mixture was stirred at room temperature for 6 hours. The solvent was evaporated to dryness and the residue was partitioned between 0.5 M HCl and DCM. The organic phase was separated and washed with NaHCO3, brine and dried over MgSO4, filtered and evaporated to afford the crude product (61 mg) as yellow oil. The product was triturated in petroleum/diethylether which yielded E5 (55 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][C:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)([C:46]([O:48][CH3:49])=[O:47])[CH2:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:57][C:54]1[CH:53]=[CH:52][C:51]([CH2:50][C:42]2([C:46]([O:48][CH3:49])=[O:47])[CH2:43][CH2:44][CH2:45][CH:40]([NH:39][C:17]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]([C:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=[C:8]4[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[O:19])[CH2:41]2)=[CH:56][CH:55]=1
Reactant: COC(=O)C1(Cc2ccc(F)cc2)CCCC(N)C1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(Cc2ccc(F)cc2)CCCC(NC(=O)c2ccc3c(c2)c(-c2ccnc(C)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 85.2 %

Procedure:
In a flask, 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (567 mg, 1.15 mmol), methyl 3-amino-1-(4-fluorobenzyl)cyclohexanecarboxylate (1.09 mmol), and HATU (622 mg, 1.64 mmol) was dissolved in dimethylformamide (3 mL). The reaction mixture was stirred for 2 minutes at room temperature. Diisopropylethylamine (0.95 mL, 5.45 mmol) was added to the reaction. The reaction was allowed to stir for an additional 1 hr. Upon completion, the reaction was quenched with water (5 mL). The water layer was extracted with ethyl acetate (20 mL) three times. The organic fractions were combined, dried with sodium sulfate, and concentrated to yield the crude product. The crude compound was purified using flash chromatography (0-100% ethyl acetate in hexane gradient) to give the title compound (690 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:19]([N:26]1[CH2:30][CH2:29][C@@H:28]([NH:31][C:32](=[O:35])[CH2:33]Br)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([N:26]1[CH2:30][CH2:29][C@@H:28]([NH:31][C:32](=[O:35])[CH2:33][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=2)[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(CBr)N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: COc1cc(O)ccc1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCC(=O)N[C@@H]2CCN(Cc3ccccc3)C2)ccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.6 %

Procedure:
(R)-(−)-1-Benzyl-3-aminopyrrolidine (5 g, 28 mmol) was dissolved in dichloromethane (10 ml). To this solution, a solution of bromoacetyl chloride (4.55 g, 28 mmol) in dichloromethane (5 ml) was added at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was filtered, washed with dichloromethane and dried in vacuo to afford 6.8 g (72%) of (3R)-N-(1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride as a solid which was used directly in the next step. 4-Hydroxy-2-methoxybenzaldehyde (2.05 g , 13 mmol) was dissolved in DMF (7 ml) and potassium carbonate (6.2 g, 45 mmol) was added followed by a suspension of the above (3R)-N-(1-Benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.0 g, 9 mmol) in DMF (16 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was then partitioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were washed with saturated sodium chloride (3×15 ml), dried (MgSO4) and concentrated in vacuo. The residue was crystallized from diethyl ether to afford 2.11 g (64%) (R)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)acetamide as a solid. M.p.: 98-101° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:15]=2)[CH2:12][C:11]([C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[N:10]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][N:23]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:22][CH2:21]3)[CH:15]=2)[CH2:12][C:11]([C:26]([F:32])([F:31])[C:27]([F:29])([F:30])[F:28])=[N:10]1
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(N3CCNCC3)c2)C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
1-(2-Chloro-phenyl)-5-[3-(piperazin-1-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Step 1, triethylamine (41.0 uL, 0.30 mmol) and methanesulfonyl chloride (8.3 mg, 0.07 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 3 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[C:14]([CH2:15][OH:16])=[N:13][CH:12]=[N:11]2)[CH:3]=1.[ClH:17].FC1C=CC(CN)=C(N2C=CC=N2)C=1>>[ClH:17].[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[N:10]1[C:14]([CH2:15][OH:16])=[N:13][CH:12]=[N:11]1
Reactant: N#Cc1ccc(F)cc1-n1ncnc1CO
Agent: Cl
Agent: NCc1ccc(F)cc1-n1cccn1
Product: NCc1ccc(F)cc1-n1ncnc1CO
Yield: 100 %

Procedure:
This compound was prepared from 4-fluoro-2-(5-hydroxymethyl-[1,2,4]triazol-1-yl)-benzonitrile by the hydrogenation method used for the preparation of 4-fluoro-2-pyrazol-1-yl-benzylamine hydrochloride. Yield: 100% (grayish green powder). HPLC rt=0.33 min. LC/MS m/z 223 (M+H). 1H NMR (DMSO-d6, 500 MHz) δ ppm 3.76 (2H, q, J=5.8 Hz, 7-NCH2), 4.55 (2H, s, 9-OCH2), 7.54–7.60 (1H, m, 5-CH), 7.62 (1H, dd, J=9, 2.6 Hz, 3-CH), 7.89 (1H, dd, J=8.7, 6.0 Hz, 6-CH), 8.26 (1H, s, 8-CH), 8.58 (3H, br.s, NH3). 13C NMR (DMSO-d6, 125.8 Hz) δ ppm 37.1 (7-NCH2), 54.2 (10-OCH2), 114.6 (d, J=24 Hz, 3-CH), 117.0 (d, J=21 Hz, 5-CH), 127.1 (d, J=3.8 Hz, 1-C), 132.2 (d, J=8.6 Hz, 6-CH), 136.9 (d, J=111 Hz, 2-C), 151.0 (9-CH), 156.3 (8-C), 161.3 (d, J=247 Hz, 4-CF). HRMS (ESI) calcd for C10H12FN4O (M+H) 223.0995. found 223.0988 (δ −3.2 ppm).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7]Cl)[N:6]=1.[CH3:9][NH2:10]>>[CH3:9][NH:10][CH2:7][C:5]1[N:6]=[C:2]([CH3:1])[S:3][CH:4]=1
Reactant: CN
Reactant: Cc1nc(CCl)cs1
Product: CNCc1csc(C)n1
Yield: 99 %

Procedure:
2-Methyl-4-(chloromethyl)thiazole (2.94 g, CAS#39238-07-8) was dissolved in 40% methylamine (39 mL, 25 equivalents) at 25° C. for 1 h. The mixture was evaporated and purified using 10% methanol/dichloromethane with 0.5% NH4OH to give 2.83 g (99%) of the amine.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:12]=[CH:11][C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:14](#[N:16])[CH3:15].N[C@H](CO)C.C(OCC)(=O)C>N1C=CC=CC=1>[S:1]([N:16]1[CH2:15][CH2:14]1)([C:4]1[CH:12]=[CH:11][C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC#N
Agent: C[C@H](N)CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 100 gallon glass-lined vessel, fitted with mechanical stirrer, addition funnel, nitrogen inlet and temperature probe, was charged with nosylchloride (52.7 kg) and acetonitrile (75L) at room temperature under nitrogen. The slurry was cooled to about 0° C. A solution of L-alaninol (7) (7.5 kg) in pyridine (32L) was added over about an hour maintaining the reaction temperature less than 10° C. during the addition, and then the mixture was aged for about two hours at about 3° C. to 5° C. Ethyl acetate (188L) and water (75L) were added and the phases were mixed. The lower aqueous layer was removed and the organic layer was washed with 1M citric acid (2×37.5L) and water (37.5L). The organic layer was cooled to about 15° C. and water (37.5L) was added. Hunig's base (N,N-diisopropylethylamine) (27L) was added for over 30 minutes. The two-phase mixture was aged at 20° C. for about an hour to complete the cyclization, and then the lower aqueous layer was removed and extracted with ethyl acetate (37.5L). The combined organic solutions were washed with 1M citric acid (2×37.5L) and water (2×37.5L). The organic layer was dried by concentration at reduced pressure and temperature at about 15° C.˜20° C. with concurrent addition of isopropylacetate (IPAC) to maintain the constant volume at about 100L. The solvent switch was completed when EA level was <5% by GC or HPLC analysis. The slurry was cooled to about 3° C. for an hour and then filtered. The cake was washed with IPAC (30L) and the solid was dried in air, which afforded about 84% isolated yield for the compound (8) (23.7 kg, 97 wt %).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][C:17]([OH:19])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][N:13]([CH3:15])[CH3:14])=[N:5]2.C(C1NC=CN=1)(C1[NH:23]C=CN=1)=O.N>Cl.CN(C)C=O>[Cl:1][C:2]1[C:3]([CH2:16][C:17]([NH2:23])=[O:19])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][N:13]([CH3:15])[CH3:14])=[N:5]2
Reactant: CN(C)Cc1cnc2ccc(Cl)c(CC(=O)O)c2n1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: CN(C)Cc1cnc2ccc(Cl)c(CC(N)=O)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
Hydrochloric acid (4 M in dioxane, 8 drops) was added to a solution of the above (6-chloro-3-dimethylaminomethyl-quinoxalin-5-yl)-acetic acid in N,N-dimethylformamide (3 ml). A solution of carbonyl diimidazole (188 mg, 1.16 mmol, 1.2 equiv) in N,N-dimethylformamide (5 ml) was added, and the mixture was stirred at room temperature for 1 hour. Concentrated aqueous ammonia (25%, 10 ml) was added, and after 10 minutes at room temperature, volatiles were removed in vacuo. The residue was purified via flash chromatography (gradient of CH2Cl2/MeOH 95:5 to 70:30) to afford the title compound (180 mg, 67%) as a foam. 1H NMR (400 MHz, d6-DMSO): δ=9.02 (s, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.54 (br s, 1H), 6.98 (br s, 1H), 4.7-4.5 (br, 2H), 4.32 (s, 2H), 2.78 (br s, 6H). MS (ES+): 279.2 (M+H)+.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:19]=[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:31][CH3:32])[CH:16]=2)[N:11]=1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C>[OH:8][CH2:9][C:10]1[N:19]=[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:31][CH3:32])[CH:16]=2)[N:11]=1
Reactant: [H][H]
Reactant: COc1ccc2nc(COCc3ccccc3)nc(NCc3ccc4c(c3)OCO4)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2nc(CO)nc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 89.5 %

Procedure:
1.5 g of 10% palladium/carbon powder was added to a solution of 1.26 g (2.93 mmol) of 2-benzyloxymethyl-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline in an ethyl acetate/ethanol (20 ml--20 ml) mixture. The obtained mixture was stirred at room temperature in a stream of hydrogen for 24 hours and filtered through Celite. The filter cake was washed with hot ethyl acetate/ethanol. The filtrate and the washings were distilled under a reduced pressure to remove the solvent. Thus 0.89 g of the title compound was obtained as a pale-yellow crystal.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+]>O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C(=O)NCCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C(=O)NCCc2ccccc2)cc1
Yield: 94.4 %

Procedure:
The product from step (a) (23.5 g 83 mmoles) was dissolved in refluxing methanol (250 ml) and a solution of sodium hydroxide (6.64 g, 166 mmoles) in water (10 ml) was added. The solid, which separated almost immediately, was filtered off, dissolved in water and acidified. The precipitate was separated, washed with water, dried and triturated with ether to give the sub-title acid (21.1 g) as a white solid mp 237°-238.5°.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[CH:25](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[CH:25]=[N:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCC(CC)Nc1cc(C)nc2c1ncn2-c1c(C)cc(C)cc1C

Procedure:
A mixture of N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine (250 mg, 0.77 mmol), trimethyl orthoformate (0.081 g, 0.766 mmol), p-toluenesulfonic acid monohydrate (0.01 g) in benzene was heated at reflux using Dean-Stark apparatus for 24 hours. Benzene was removed and toluene was added and an excess of trimethyl orthoformate (0.084 ml) was added to the reaction mixture. The mixture was heated at reflux overnight. The mixture was quenched with water, sat. NaHCO3, extracted with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated to dryness. After purification, the title compound was isolated as a white crystal, mp 78–80° C.