Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C@:11]1([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:13][O:12]1.C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[N:3]([CH2:13][C@:11]([OH:12])([CH3:10])[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)CO2)CC1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Yield: 45 %

Procedure:
To the solution of 2-Chloro-4-nitro-1H-imidazole (89.4 g, 606 mmol) and tert-butyl (S)-4-(2-methyloxiran-2-ylmethyl)piperazine-1-carboxylate (119 g, 466 mmol) in ethanol (475 ml), sodium hydrogen-carbonate (58.7 g, 699 mmol) was added followed by stirring under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added water. The mixture was extracted with ethyl acetate, and the extract was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was dispersed into ethyl acetate, and filtered off to afford a solid. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (n-hexane/acetone=3/1) to afford a solid. The solids were combined and dried under reduced pressure to afford tert-butyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-piperazine-1-carboxylate (84.7 g, yield 45%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:19][C:20]1[S:21][C:22]2[C:23](=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:26]=[C:27]([F:29])[CH:28]=2)[N:24]=1>C(Cl)Cl>[NH2:19][C:20]1[S:21][C:22]2[C:23](=[C:25]([S:30]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=3)(=[O:32])=[O:31])[CH:26]=[C:27]([F:29])[CH:28]=2)[N:24]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Nc1nc2c(S(=O)(=O)Cl)cc(F)cc2s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2cc(F)cc3sc(N)nc23)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of the ethyl 4-aminobenzoate (413 mg, 2.5 mmol) in 20 mL of DCM was added pyridine (600 mg, 7.5 mmol) and 2-amino-6-fluorobenzo[d]thiazole-4-sulfonyl chloride (668 mg, 2.5 mmol). The resulting mixture was stirred at 50° C. overnight. After removal of DCM, the residue was partitioned between water and EtOAc. The organic layer was washed with 2 N HCl, water and brine, dried over Na2SO4 and concentrated to give crude product, which was purified by chromatography to give pure compound 26C. 1H NMR (CHLOROFORM-d) δ: 8.10 (s, 1H), 7.93-7.82 (m, 2H), 7.59 (dd, J=8.2, 2.6 Hz, 1H), 7.47 (dd, J=7.5, 2.6 Hz, 1H), 7.20-7.09 (m, 2H), 5.73 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H). LC-MS: m/z 396.5 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2ccc(Cl)cc2)cc1
Yield: 35 %

Procedure:
Following a procedure similar to that described in Example 12, but using 2 g of 2-amino-1-(4-chlorophenyl)ethanol (prepared as described in Preparation 12), 3.11 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 50 ml of absolute methanol and 2.7 g of sodium cyanoborohydride, 1.54 g of the title compound were obtained as crystals, melting at 78°-79° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>>[CH:32]1([C:35]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=5[O:27][CH2:28][CH:29]5[CH2:30][CH2:31]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:5][CH2:6]2)=[O:36])[CH2:34][CH2:33]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)NC4CCN(C(=O)C5CC5)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A152) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[CH2:23]([C@@H:30]1[CH2:35][C@@H:34]([N:36]([CH2:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]=[CH:46][CH:45]=2)[C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])[CH2:33][CH2:32][NH:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[F:54][C:55]([F:70])([F:69])[C:56]1[CH:57]=[C:58]([CH:62]=[C:63]([C:65]([F:68])([F:67])[F:66])[CH:64]=1)[C:59](O)=[O:60]>C(Cl)Cl>[CH2:23]([C@@H:30]1[CH2:35][C@@H:34]([N:36]([CH2:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]=[CH:46][CH:45]=2)[C:37](=[O:42])[C:38]([F:40])([F:41])[F:39])[CH2:33][CH2:32][N:31]1[C:59](=[O:60])[C:58]1[CH:62]=[C:63]([C:65]([F:66])([F:67])[F:68])[CH:64]=[C:56]([C:55]([F:54])([F:69])[F:70])[CH:57]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
143 mg (561 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine are added to a solution of 200 mg (467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine and 113 mg (561 mmol) of 3,5-bis-(trifluoromethyl)-benzoic acid in 3 ml of methylene chloride, and the reaction mixture is left to stir at room temperature for 16 hours. It is then diluted with methylene chloride, and the organic phase is washed once each with 10% strength citric acid, 1N sodium bicarbonate solution and with brine, dried over magnesium sulfate and evaporated to dryness. The yellowish foam is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (1000:50:1). The title compound is obtained as yellow oil. TLC: methylene chloride/methanol/conc. ammonia (1000: 50:1) Rf =0.34, FD-MS: M+ =667.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[CH3:29]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[O:26])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCNCc1ccccn1
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: CCN(Cc1ccccn1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[N:13][C:14]([NH:17][CH2:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)([CH3:21])[CH3:20])=[CH:15][N:16]=2)[CH:8]=[CH:9][CH:10]=1>CN1C(=O)CCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]([CH3:21])([CH3:20])[CH2:18][NH:17][C:14]2[N:13]=[N:12][C:11]([C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:1]#[N:2])=[N:16][CH:15]=2)=[CH:23][CH:24]=1
Reactant: [C-]#N
Reactant: CC(C)(CNc1cnc(-c2cccc(Cl)c2)nn1)c1ccc(F)cc1
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(CNc1cnc(-c2cccc(C#N)c2)nn1)c1ccc(F)cc1
Temperature: 200 °C
Yield: 48.7 %

Procedure:
To a microwave vial containing NiBr2 (280 mg, 1.3 mmol) and NaCN (120 mg, 2.5 mmol) was added a solution of 3-(3-chlorophenyl)-N-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-triazin-6-amine (450 mg, 1.3 mmol) in NMP (4.0 mL). The vial was purged with nitrogen and sealed. The mixture was heated to 200° C. in a microwave for 25 min and allowed to cool to room temperature. The solution was diluted with EtOAc/ether (1:1), washed with water (3×), dried over Na2SO4 and evaporated to dryness. Purification using silica gel chromatography (0-65% EtOAc/hexanes) gave the desired product (220 mg) as an off white foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH3:19])[N:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[OH:20].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH3:19])[N:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[O:20][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOCn1nccc1C(=O)c1ccc(O)c(Cl)c1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCn1nccc1C(=O)c1ccc(OCC(=O)OCC)c(Cl)c1Cl
Yield: 88.9 %

Procedure:
1.67 g of 2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenol, 1.15 g of ethyl bromoacetate and 1.68 g of potassium carbonate are added to 60 ml of acetone, and the mixture is refluxed for 1 hour. The reaction mixture is filtered and the filtrate is evaporated to remove solvent. The residue is dissolved in benzene, and the solution is treated with activated charcoal and evaporated to give an oil, which is then crystallized from isopropyl ether to give 1.89 g of ethyl [2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenoxy]acetate.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.F[C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][N:20]=1>O>[I:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([O:15][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)[CH:24]=1
Reactant: Fc1cc(I)ccn1
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cc(I)ccn2)cc1
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
With cooling with ice, sodium hydride (60% oily, 4.93 g, 0.188 mmol) was added to a DMF (250 mL) solution of 4-methoxybenzyl alcohol (17.04 g), and stirred for 30 minutes. 2-Fluoro-4-iodopyridine (25.0 g) was added, and stirred at room temperature for 2 hours. Water was added to the reaction liquid, and extracted with diethyl ether. The organic layer was washed with saturated saline, and dried with anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, then diisopropyl ether was added to the obtained residue, and the obtained solid was collected by filtration to obtain the entitled compound (26.15 g, 68%).
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([CH3:16])[CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:34][C@@H:35]([CH2:54][C:55]1[CH:60]=[C:59]([F:61])[CH:58]=[C:57]([F:62])[CH:56]=1)[CH2:36][NH:37][C@H:38]([C:40]([NH:42][C@H:43]([C:47]([NH:49][CH2:50][CH:51]([CH3:53])[CH3:52])=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[CH3:39]>CN(C=O)C>[F:61][C:59]1[CH:60]=[C:55]([CH2:54][C@H:35]([NH:34][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([CH3:16])[CH:15]=[C:7]([C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:17][CH2:18][CH3:19])=[O:6])[CH:8]=2)[CH2:36][NH:37][C@H:38]([C:40]([NH:42][C@H:43]([C:47]([NH:49][CH2:50][CH:51]([CH3:53])[CH3:52])=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[CH3:39])[CH:56]=[C:57]([F:62])[CH:58]=1
Reactant: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)O)c1
Reactant: CC(C)CNC(=O)[C@@H](NC(=O)[C@H](C)NC[C@@H](N)Cc1cc(F)cc(F)c1)C(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@H](CN[C@@H](C)C(=O)N[C@H](C(=O)NCC(C)C)C(C)C)Cc2cc(F)cc(F)c2)c1
Reaction time: 1 h
Yield: 69.5 %

Procedure:
3-[(Dipropylamino)carbonyl]-5-methylbenzoic acid, (90 mg, 0.34 mmol) is combined with EDC(65 mg, 0.34 mmol) and HOBT (46 mg, 0.34 mmol) in 3 mL of DMF and stirred under nitrogen for 1 h. This solution is then added to a solution of N-[(2S)-2-amino-3-(3,5-difluorophenyl)propyl]-L-alanyl-N1-isobutyl-L-valinamide (88 mg, 0.21 mmol) in 1 mL of DMF. The reaction is continued for 3 days at ambient temperature. It is then quenched with 1 N KH2PO4 and diluted with ethyl acetate containing about 1% of methanol. The organic phase is washed with water, 1 N NaHCO3, and brine, and dried over Na2SO4. Concentration and chromatography over silica gel, eluting with 4% to 6% methanol in dichloromethane, affords 96 mg (0.146 mmol, 69%) of the title compound as a light tan solid. 1H NMR (CDCl3) δ 7.75 (d, J=9 Hz, 1H), 7.54 (s, 1H), 7.37 (s, 1H), 7.21 (s, 1H), 7.16 (d, J=8 Hz, 1H), 6.84 (m, 2H), 6.70 (m, 1H), 6.64 (m, 1H), 4.19 (dd, J=7, 9 Hz, 1H), 4.05 (m, 1H), 3.5-3.4 (m, 2H), 3.33 (dd, J=6, 14 Hz, 1H), 3.19-3.02 (m, 5H), 2.88 (dd, J=6, 14 Hz, 1H), 2.68 (dd, J=4, 13.5 Hz, 1H), 2.58 (m, 1H), 2.37 (s, 3H), 1.96 (m, 1H), 1.75-1.64 (m, 4H), 1.50 (m, 2H), 1.35 (d, J=7 Hz, 3H), 0.99 (t, J=7 Hz, 3H), 0.91 (d, J=7 Hz, 3H), 0.86 (m, 9H), 0.71 (t, J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:7]=[C:6]1[CH2:18][CH2:19][CH3:20].[N+:25]([O-])([OH:27])=[O:26]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[C:7]([N+:25]([O-:27])=[O:26])=[C:6]1[CH2:18][CH2:19][CH3:20]
Reactant: CCCc1cc2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: CCCc1c([N+](=O)[O-])c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 1-(2-chlorobenzyl)-2-propylindole-6-carboxylate (200 mg) in trifluoroacetic acid (2 ml) was added concentrated nitric acid (0.3 ml) at 0° C. After stirred at 0° C. for 30 minutes, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with a mixture of ethyl acetate and hexane (1:3) to give methyl 1-(2-chlorobenzyl)-3-nitro-2-propylindole-6-carboxylate (73 mg) as pale yellow crystals.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)#[N:4].Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1>>[C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][CH2:31][N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]=[CH:18][N:17]=3)[C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)#[N:4]
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Product: COc1cc2c(C3C(=O)Nc4cc(C#N)ccc43)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.3 %

Procedure:
Sodium hydride (80 mg, 2.07 mmol) was added to a solution of 6-cyanooxindole (280 mg, 1.78 mmol), (prepared as described for the starting material in Example 57), in dry, degassed DMF (10 ml) and the suspension stirred for 15 minutes at ambient temperature. A solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (200 mg, 0.59 mmol), (prepared as described for the starting material in Example 5), in a dry, degassed mixture of DMF (2 ml) and THF (2 ml) was added dropwise and the reaction mixture was heated at 60° C. for 3 hours. The mixture was allowed to cool, the solvents were removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase extracted with ethyl acetate (50 ml×3). The ethyl acetate fractions were combined, dried (MgSO4), the solvent removed by evaporation and the residue was purified by flash column chromatography eluting with methylene chloride/methanol (100/13). The purified product was triturated in boiling ether and the solid product collected by filtration to give 4-(6-cyanooxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (36 mg, 13%) as an orange solid.
Reaction SMILES: C(S([NH:7][C:8]([CH:18]1[CH2:20][CH2:19]1)([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O)(C)(C)C.O1CCOCC1>Cl.C(OCC)(=O)C>[NH2:7][C:8]([CH:18]1[CH2:19][CH2:20]1)([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11]
Reactant: CC(C)(C)OC(=O)CC(C)(NS(=O)C(C)(C)C)C1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(C)(N)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
tert-butyl 3-(tert-butylsulfinylamino)-3-cyclopropyl-butanoate (example 229a, 1.93 g, 6.36 mmol) was dissolved in a 4M solution of hydrochloric acid in dioxane (4.77 ml, 19.1 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was then diluted with ethyl acetate and poured into a separatory funnel. The organic phase was extracted with a 2M aqueous solution of sodium carbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness to yield the title compound (1.08 g, 85%) as a crude oil which was used without any purification. MS (ESI, m/z): 200.3 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]O)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:41]>>[Cl:41][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:4]1[CH2:3][CH:2]([CH3:1])[O:7][CH:6]([CH3:8])[CH2:5]1
Reactant: CC1CN(CCCCCCCCCCCO)CC(C)O1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC1CN(CCCCCCCCCCCCl)CC(C)O1

Procedure:
This intermediate (5.1 g.) was prepared using the procedure described in Example 4c except using 9.35 g. (0.033 mole) of 2,6-dimethyl-4-(11-hydroxyundecyl)morpholine, 9.43 g. (0.036 mole) of triphenylphosphine, and 70 ml. of carbon tetrachloride.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:22])=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCNCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a mixture of diethylamine (89.1 mL), triethylamine (120.2 mL) and CH2Cl2 (500 mL) cooled in an ice-bath was added dropwine p-anisoyl chloride (133.8 g) over 40 minutes. The reaction mixture was stirred at room temperature for 40 minutes, the mixture was filtered, washed with ether and the solvent was removed in vacuo. Ether was added, then water to the residue, then the organic layer was separate and washed with 5% NaoH, then in HCl, then brine and then was dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by kugelrohr distillation at 140°-180° C. under high vacuum to afford 163.8 g of 4-methoxy-N,N-diethylbenzamide, m.p. 40°-42° C.
Reaction SMILES: [CH:1]1([CH:6]2[O:10][B:9]([OH:11])[C:8]3[CH:12]=[C:13]([NH:16][C:17](=[O:28])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4C(F)(F)F)[CH:14]=[CH:15][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:29]C1C=CC=CC=1C(Cl)=O>>[CH:1]1([CH:6]2[O:10][B:9]([OH:11])[C:8]3[CH:12]=[C:13]([NH:16][C:17](=[O:28])[C:18]4[CH:23]=[CH:22][C:21]([F:29])=[CH:20][CH:19]=4)[CH:14]=[CH:15][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Nc1ccc2c(c1)B(O)OC2C1CCCC1)c1ccccc1C(F)(F)F
Reactant: O=C(Cl)c1ccccc1F
Product: O=C(Nc1ccc2c(c1)B(O)OC2C1CCCC1)c1ccc(F)cc1

Procedure:
The title compound was prepared using a procedure similar to that of N-(3-cyclopentyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamide with 2-fluorobenzoyl chloride replacing 2-trifluoromethylbenzoyl chloride. Data: LCMS (M/Z): 340 (M+H); 1H NMR (acetone) δ: 9.54 (br. s., 1H), 8.17 (d, J=2.0 Hz, 1H), 8.03-8.11 (m, 3H), 7.80 (dd, J=8.3, 2.1 Hz, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.22-7.30 (m, 2H), 5.12 (d, J=4.8 Hz, 1H), 2.26-2.35 (m, 1H), 1.81-1.91 (m, 1H), 1.62-1.73 (m, 2H), 1.49-1.57 (m, 2H), 1.40-1.49 (m, 1H), 1.30-1.39 (m, 1H), 1.09-1.20 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]([OH:15])[CH2:12][S:11](=[O:17])(=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][C:13](=[O:15])[CH2:12][S:11](=[O:16])(=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCS(=O)(=O)CC(O)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCS(=O)(=O)CC(=O)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4-N-(t-Butyloxycarbonyl)-1,1-dioxo-6-hydroxy -2,3,4,5,6,7-hexahydro-1,4-thiazepine (10.0 g, 37.7 mmole) from Example 5, was dissolved in 110 mL of acetone, cooled to 0° C. and treated with 18.8 mL of freshly prepared Jones reagent. The reaction was stirred at ambient temperature for three hours and then treated with 5 mL of methanol. After 15 minutes, the reaction was filtered through magnesium sulfate and the filtrate immediately concentrated. The residue was filtered through a pad of silica gel using 3:1 chloroform-ethyl acetate to obtain the produce (9.67 g, 87%) D.C.I.M.S. 264(M+H) M.P. 172°-173° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11])([O-:3])=[O:2].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C(O)C>[OH:14][C:15]1[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[N:11]=[CH:22][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: NNc1ccccc1[N+](=O)[O-]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccccc2[N+](=O)[O-])c1O
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
102 g (2-nitrophenyl)hydrazine and 142 g (Ethoxymethylene)propanedioic acid, diethyl ester are dissolved in 300 ml ethanol and refluxed for 20 hours. After cooling the clear red solution is evaporated and the solvent distilled off. The remaining crystalline residue (168 g) is added to 400 g PPA (polyphosphoric acid) at a temperature of 80° C. The reaction is completed by heating the solution for 10 minutes to 120° C. The solution is then immediately poured on 2 kg ice and stirred for 30 minutes. After filtration the residue is recrystallized from n-propanol to yield 80 g of 5-hydroxy-1-(2-nitrophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester with a melting point of 157°-160° C.; yellow crystals.