Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([C@@H:9]3[CH2:13][C@H:12]([CH3:14])[CH2:11][N:10]3C(OC(C)(C)C)=O)=[N:8][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[I:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([C@@H:9]3[CH2:13][C@H:12]([CH3:14])[CH2:11][NH:10]3)=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@H]1C[C@@H](c2nc3cc(I)ccc3[nH]2)N(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN[C@H](c2nc3cc(I)ccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a stirring solution of tert-butyl (2S,4S)-2-(5-iodo-1H-benzimidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (3.70 g, 8.659 mmol) in dichloromethane (34 mL) is added TFA (17.22 mL, 223.5 mmol) and stirred at rt for 1 h. The reaction mixture is concentrated, azeotroped 2× with toluene and dried in vacuo. The residue is diluted with dichloromethane (200 mL), washed 2× with saturated sodium bicarbonate and brine and then dried over sodium sulfate. The organic is evaporated to give 5-iodo-2-[(2S,4S)-4-methylpyrrolidin-2-yl]-1H-benzimidazole (2.32 g, 82%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH:11]=[CH:10]2
Reactant: Cc1ccc2nc(Cl)ccc2c1NC(=O)CC1CCCCC1
Reactant: C1CNCCN1
Product: Cc1ccc2nc(N3CCNCC3)ccc2c1NC(=O)CC1CCCCC1
Temperature: 25 °C
Yield: 44.1 %

Procedure:
Prepared according to the method of example 2, using N-(2-Chloro-6-methyl-5-quinolinyl)-cyclohexaneacetamide (Example 15(a)) (0.2 g) and piperazine (0.163 g). The reaction was cooled to room temperature, the resulting solid collected by filtration and recrystallised from methanol to afford the title compound (0.102 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[CH2:12]([O:14][P:15]([CH2:20]O)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:12]([O:14][P:15]([CH2:20][O:10][C:8]1[CH:9]=[C:2]([Cl:1])[C:3]([CH:4]=[O:5])=[C:6]([Cl:11])[CH:7]=1)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:13]
Reactant: CCOP(=O)(CO)OCC
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(COc1cc(Cl)c(C=O)c(Cl)c1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-dichloro-4-hydroxy-benzaldehyde (190 mg, 1.0 mmol) and hydroxymethyl-phosphonic acid diethyl ester (278 mg, 1.0 mmol) in THF (8 mL) was added PPh3-resin (553 mg, 2.13 mmol/g) and DEAD (0.54 ml of 40% solution, 1.2 mmol). The suspension was stirred at ambient temperature overnight then the reaction mixture was filtered and partioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with MgSO4, filtered and concentrated. Purification by flash chromatography using heptane/EtOAc (1:3) gave (3,5-dichloro-4-formylphenoxymethyl)-phosphonic acid diethyl ester as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:31]3[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=3)([C:21]3[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=1.Cl.[CH3:38][NH:39][O:40][CH3:41]>CN(C)C=O>[Cl:18][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:31]3[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=3)([C:21]3[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=[C:2]([N:39]([O:40][CH3:41])[CH3:38])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNOC
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Agent: Cl
Solvent: CN(C)C=O
Product: CON(C)c1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1-c1ccccc1
Temperature: 100 °C

Procedure:
(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl) [6-(trifluoromethyl)pyridin-3-yl]methanol (200 mg, 0.378 mmol, Example 66), N,O-dimethylhydroxylamine hydrochloride (376 mg, 3.78 mmol), and dimethylformamide (2 mL) were combined in a reaction tube which was then sealed and heated to 100° C. for 48 hours. Analysis shows desired product, but also the presence of starting material. Additional N,O-dimethylhydroxylamine hydrochloride (190 mg, 0.195 mmol) was added and the contents were heated for an additional 24 hours. The contents were then cooled, transferred to a separatory funnel, diluted with EtOAc and extracted with a saturated, aqueous NH4Cl solution, followed by deionized water (4×). The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C28H23ClF3N5O2, 553.1; m/z found, 554.2 [M+H]+; 1H NMR (400 MHz, CD3OD) δ ppm 8.79 (d, J=2.1 Hz, 1H), 8.19 (d, J=1.9 Hz, 1H), 8.02 (dd, J=8.2, 1.9 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.75-7.68 (m, 2H), 7.48 (t, J=7.4 Hz, 2H), 7.40 (ddd, J=7.4, 3.9, 1.3 Hz, 1H), 7.32-7.24 (m, 2H), 6.35 (s, 1H), 3.48 (s, 3H), 3.07 (s, 3H), 2.77 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=O.ClC1C=C(C([NH:21][C@H:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][C@H:23]2[O:33][CH2:34][CH2:35][CH3:36])=O)NC=1C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:21][C@@H:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][C@@H:23]1[O:33][CH2:34][CH2:35][CH3:36])=[O:11]
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Reactant: CCCO[C@@H]1CN(C(=O)OCC)CC[C@@H]1NC(=O)c1cc(Cl)c(C)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (WO2006087543, 1.77 g, 9.13 mmol) and ethyl (3S,4R)-4-amino-3-propoxypiperidine-1-carboxylate (see Intermediate 73, 2.1 g, 9.13 mmol) in dichloromethane (150 mL) was added N-Hydroxybenzotriazole (1.67 g, 10.95 mmol) and N-methylmorpholine (2.76 g, 27.39 mmol). The reaction mixture was stirred for 1 h at room temperature and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.023 g, 16.43 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 2N hydrochloric acid (30 mL) and the layers were separated. The organic layer was washed with sodium bicarbonate (40 mL), water (60 mL) and finally with brine successively, and dried over anhydrous sodium sulphate, filtered, and concentrated under vacuum to afford ethyl (3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate 3.3 g (89.1%) as solid.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[OH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1I.Cl>CN1CCCC1=O>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:2]=1[S:1][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:14]=1[OH:13])[C:18]([OH:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(CO)c(S)c1
Reactant: O=C(O)c1ccc(O)c(I)c1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(O)c(Sc2cc([N+](=O)[O-])ccc2CO)c1
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
A mixture of 2-mercapto-4-nitrobenzyl alcohol 9.49 g, 18.86 mmoles), 4-hydroxy-3-iodo-benzoic acid (4.67 g, 17.69 mmoles), red cuprous oxide (1.35 g, 9.44 mmoles) and 1-methyl-2-pyrrolidinone (40 ml) was heated under a N2 atmosphere. The mixture became a thick slurry at 90° but at 130° had become a dark red solution. After 1/2 hour at 140° TLC showed that the reaction was finished. The mixture was poured onto 2N HCl (200 ml) and after stirring for a few minutes it was extracted 4× with EtOAc. The EtOAc extracts were washed with water, then extracted 4× with 1N NaOH. The aqueous extracts were washed once with EtOAc then acidified and the resulting solid filtered, washed with water and dried to yield 4.65 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH3:17])=[O:16])=[C:10]([N+:18]([O-])=O)[CH:9]=2)=[N:5][NH:4][C:3]1=[O:21].C(O)(=O)C>C(O)C>[CH3:1][CH:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH3:17])=[O:16])=[C:10]([NH2:18])[CH:9]=2)=[N:5][NH:4][C:3]1=[O:21]
Reactant: CC(=O)Nc1ccc(C2=NNC(=O)C(C)C2)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)Nc1ccc(C2=NNC(=O)C(C)C2)cc1N

Procedure:
2.9 gm of 4-methyl-6-(3'-nitro-4'-acetamino-phenyl)-4,5-dihydro-3(2H)-pyridazinone were hydrogenated in 80 ml of ethanol and 20 ml of glacial acetic acid at room temperature and 5 atmospheres in the presence of 1.5 gm of palladizedcoal. The catalyst was then filtered off, the filtrate was evaporated, and the residue was used as such in the next step.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([O:17][CH3:18])[C:6]([O:15][CH3:16])=[N:7]2.[CH2:19](C([SnH3])=C(CCCC)CCCC)[CH2:20]CC.[Cl-].[Li+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][O:15][C:6]1[C:5]([O:17][CH3:18])=[N:4][C:3]2[C:8](=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:2]=2[CH:19]=[CH2:20])[N:7]=1
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Reactant: COc1nc2cc([N+](=O)[O-])cc(Br)c2nc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12
Temperature: 100 °C

Procedure:
A mixture of 3.14 g (1 mmol) of 5-bromo-2,3-dimethoxy-7-nitro-quinoxaline, 6.34 g (2 mmol) of tributylvinylstannane, 1.26 g (3 mmol) of lithium chloride and 1.4 g (0.2 mmol) of bis(triphenylphosphine)-palladium(II) chloride in 20 ml of dimethylformamide is heated for 2 hours at 100° C. The mixture is cooled to room temperature and concentrated to dryness by evaporation under reduced pressure. Purification by flash chromatography using toluene as eluant yields the title compound in the form of a slightly yellowish solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:22][CH2:23][CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([O:10]CC)=[O:9])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:22][CH2:23][CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCCC(NC(=O)Cc1ccc(C=CC(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(NC(=O)Cc1ccc(C=CC(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
A solution of ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-cinnamate (0.49 g, 1 mmol) in ethanol (10 ml) is stirred together with 1N sodium hydroxide solution (2 ml) for 3 days at ambient temperature. The mixture is then concentrated by evaporation in vacuo, water and a few drops of methanol are added to the evaporation residue and this is then adjusted to pH 6 with 1N acetic acid. The precipitate is filtered off, dried and recrystallised from ethyl acetate.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16](=[O:24])[C:17]([Cl:23])=[C:18]([Cl:22])[C:19](O)=[O:20])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]1[CH3:36])[CH3:26]>C(OC(=O)C)(=O)C>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]2([C:29]4[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:27]([CH2:25][CH3:26])[C:28]=4[CH3:36])[O:24][C:19](=[O:20])[C:18]([Cl:22])=[C:17]2[Cl:23])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(Cl)=C(Cl)C(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Reactant: CCn1c(C)cc2ccccc21
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(c3c(-c4ccccc4)[nH]c4ccccc34)OC(=O)C(Cl)=C2Cl)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 7.0 g (0.02 mole) of 4-(2-phenyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid (prepared in part A above), 3.5 g (0.02 mole of 1-ethyl-2-methylindole and 200 ml of acetic anhydride was stirred at ambient temperature in an atmosphere of air for approximately seventeen hours. The pale blue solid that formed was collected by filtration and dried in vacuo at 60° C. to obtain 5-(2-phenyl-3-indolyl)-5-(1-ethyl-2-methyl-3-indolyl)-3,4-dichloro-2(5H)-furanone (Formula V: R=Y=Y1 =H; R1 =C6H5 ; R2 =CH3CH2 ; R3 =CH3) as a tan-colored solid which started to sinter at 213° C. and was completely melted at 225° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH2:12][C:13]#[CH:14])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].[I:17]I>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][O:11][CH2:12][C:13]#[C:14][I:17])=[CH:7][CH:8]=1)#[N:2]
Reactant: II
Reactant: C#CCOCOc1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(OCOCC#CI)cc1
Reaction time: 3 h
Yield: 80.5 %

Procedure:
1 -Cyano-4-[(2-propynyloxy)methoxy]benzene (Intermediate II-i) (9.4 g, 0.05 mol) prepared in the above example 4 and 48% w/v aqueous sodium hydroxide solution (11.3 g) were added to methanol (75 g). Iodine (14.0 g, 0.055 mol) was then added to the solution in several portions while maintaining the inner temperature below 10° C. The reaction mixture was stirred for further 3 hours and the solvent was then evaporated off. The residue was extracted with toluene (10 ml) and the toluene layer was washed with distilled water. Toluene was then evaporated off to obtain a crude reaction product (15.3 g). The crude reaction product (15.3 g) was recrystallized from hexane (50 ml) to obtain the desired 1-cyano-4-[[(3-iodo-2-propynyl)oxy]methoxy]benzene (Derivative III-i)(12.6 g, 94% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9]Br.O.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([Br:9])[CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: Oc1ccccc1F
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(Br)cc1F
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a stirred solution of 2-fluorophenol (22.4 g, 0.2 mole) in methylene chloride (250 ml) which was cooled to ~3° C. in an ice bath, was added, all at once, bromine (31.97 g, 0.2 mole). The resulting solution was stirred at ice bath temperature for two hours and then at room temperature for 1 hour. The mixture was poured into water (600 ml) containing excess sodium bisulfite. The organic phase was separated and the aqueous phase was washed with additional methylene chloride (200 ml). The combined organic extracts were washed with saturated sodium bicarbonate, dried (MgSO4) and the solvent evaporated to give the desired 2-fluoro-4-bromophenol as a colorless oil (34.5 g, 90%). The NMR (CDCl3) was consistent with the assigned structure. The gc of this material showed that it contained only a trace of the 2,6-isomer. This material was used directly in the following step without additional purification.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:27][N:28]([CH3:49])[CH2:29][CH2:30][N:31](CCN(C)C)[S:32]([C:35]1[S:36][C:37]([Cl:43])=[C:38]([N+:40]([O-])=O)[CH:39]=1)(=[O:34])=[O:33]>>[Cl:43][C:37]1[S:36][C:35]([S:32](=[O:34])(=[O:33])[NH:31][CH2:30][CH2:29][N:28]([CH3:49])[CH3:27])=[CH:39][C:38]=1[NH:40][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:1])([F:25])[F:26])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:13]
Reactant: CN(C)CCN(CCN(C)C)S(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)CCNS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.14) according to general procedure II.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH2:14])[C:8]([OH:21])=[C:7]([CH3:22])[C:6]=1[CH3:23])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Ca+2].[I:29](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>O1CCCC1.CO>[C:1]([O:4][C:5]1[C:6]([CH3:23])=[C:7]([CH3:22])[C:8]2[O:21][CH:13]([CH2:14][I:29])[CH:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9]=2[C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: O=I(=O)Cl
Reactant: C=CC(c1ccccc1)c1c(C)c(OC(C)=O)c(C)c(C)c1O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(c1ccccc1)C(CI)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a suspension of 4-hydroxy-2,3,6-trimethyl-5-(1-phenyl-2-propenyl)phenyl acetate (5.10 g, 16.4 mmol) and calcium carbonate (2.13 g, 21.3 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was added benzyltrimethylammonium dichloroiodate (6.28 g, 18.0 mmol) slowly. The mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with 10% aqueous sodium hydrogen sulfite, water, an aqueous saturated solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, treated with activated carbon, filtrated and the filtrate was concentrated in vacuo to provide 5.30 g of 2-iodomethyl-4,6,7-trimethyl-3-phenyl-2,3-dihydrobenzofuran-5-yl acetate. A mixture of this compound (5.30 g, 12.1 mmol) and 1,8-diazabicyclo[5,4,0]-7-undecene (9.0 m, 60.0 mmol) in toluene (20 mL) was stirred under an argon atmosphere at 100° C. for 3 hours. To that mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with 2N hydrochloric acid, and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain the title compound (4.0 g, yield 79%). This was oily.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6](N)[CH:7]=1.N([O-])=O.[Na+].[BrH:14]>O>[Br:14][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH3:9]
Reactant: Cc1ccc(Cl)cc1N
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Cl)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-chloro-2-methylbenzenamine (50 g, 0.355 mol) was dissolved in HBr solution (1.5 M, 100 mL) and cooled to 0° C., a solution of NaNO2 (27.6 g, 0.4 mol) in water (200 mL) was added dropwise. After addition, the mixture was stirred for 1 hr. In another flask CuBr (30 g, 0.21 mol) was added to HBr solution (1.5 M, 30 mL) and heated to 60° C., then the mixture was added to the above solution. The mixture was heated to reflux for 1 hr then cooled to rt. The reaction was quenched with water (500 mL), the aqueous layer was extracted 3 times with CH2Cl2, dried over Na2SO4, solvent removal and purification by column chromatography afforded 2-bromo-4-chloro-1-methylbenzene (53 g, 0.26 mol). 1H NMR (CDCl3, 400 MHz) δ 7.53 (s, 1H), 7.20-7.10 (m, 2H), 2.36 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:4]#[N:5].[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(#N)C>[C:19]([O:1][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:4]#[N:5])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: N#CC(CO)c1cccc(Oc2ccccc2)c1
Solvent: CC#N
Product: CC(=O)OCC(C#N)c1cccc(Oc2ccccc2)c1
Yield: 86 %

Procedure:
A 175 mg (0.738 mmol) sample of the above 3-hydroxy-2-(3-phenoxyphenyl)propanenitrile was acylated with acetic anhydride (74 μL) in acetonitrile (300 μL) using the procedure described in Example 5 to give 147 mg (86% yield) of 3-acetoxy-2-(3-phenoxyphenyl)propanenitrile as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9]O)[CH:2]=1.P(Cl)(Cl)([Cl:13])=O.[ClH:16]>C(OCC)(=O)C.[OH-].[Na+]>[ClH:13].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][Cl:16])[CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCCCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: ClCCCc1cccnc1

Procedure:
3-(3-Pyridyl)propyl chloride hydrochloride was prepared in quantitative yield by reacting 3-(3-pyridyl)propanol with phosphorus oxychloride in ethyl acetate at reflux temperature. The free base was generated by dissolving the hydrochloride in a 10% sodium hydroxide solution and extracting with an organic solvent (toluene or ether).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[OH:22][CH2:23][CH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][C:28](=[O:34])[NH:29]2>>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:27]3\[C:28](=[O:34])[NH:29][C:30]4[C:26]\3=[C:25]([CH2:24][CH2:23][OH:22])[CH:33]=[CH:32][CH:31]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4cccc(CCO)c43)c(C)c2C1=O
Yield: 29.5 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-5-(2-diethylamino-ethyl)-2-[4-(2-hydroxy-ethyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 17 (18 mg, yield 29.5%) as a yellow solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:14]=2)[CH:9]=[N:8]1.[CH3:47][C@H:48]1[CH2:50][O:49]1>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH2:47][C@@H:48]([OH:49])[CH3:50])[CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:35])=[O:36])[CH:14]=2)[CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (230 mg, 0.349 mmol) was alkylated using (S)-2-methyloxirane (41 mg, 0.69 mmol) DIPEA (136 mg, 10 mmol) and ethanol (5 mL) to get 200 mg (crude) of the titled compound.