Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]([CH:38]=[CH:39][CH:40]=3)[O:20][C:21]3[N:25](CC4C=CC(OC)=CC=4)[N:24]=[N:23][C:22]=3[C:35](O)=[O:36])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:40]=[CH:39][C:38]4[C:35](=[O:36])[C:22]5[NH:23][N:24]=[N:25][C:21]=5[O:20][C:19]=4[CH:18]=3)[CH2:11][CH2:12]2)=[CH:41][CH:42]=1
Reactant: COc1ccc(Cn2nnc(C(=O)O)c2Oc2cccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=c1c2ccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)cc2oc2nn[nH]c12
Reaction time: 4 h
Yield: 35 %

Procedure:
The carboxylic acid from example 3 (10.0 g, 16.89 mmol) was dissolved in dry dichloromethane (450 ml) and thionyl chloride (2.742, 20.27 mmole) was added together with 10 drops of N,N-dimethylformamide. The mixture was refluxed with stirring for 4 hours under nitrogen and the solvent and excess thionyl chloride were removed in vacuo. Fresh dichloromethane (500 ml) was added and the freshly ground anhydrous aluminium chloride (7.88 g, 59.1 mmole, 3.5 equiv.) was added in three portions (over 20 minutes) at room temperature whilst under nitrogen. After a further 30 minutes the supernatant was separated from the brown oil which separated and 2M hydrochloric acid was added (250 ml). Trituration afforded a white solid which was partitioned between water and dichloromethane. Evaporation of the dried organic phase afforded crude title compound which after silica gel chromatography gave 2.68 g (35%) of material identical with that previously described in European Pat. No. 34,004.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][O:31][CH2:32][CH3:33])[N:24]([CH2:25][CH2:26][CH2:27][C:28]#[CH:29])[C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][O:31][CH2:32][CH3:33])[N:24]([CH2:25][CH2:26][CH2:27][C:28]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:29]=3)[C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: ON=C(Cl)c1ccccc1
Reactant: C#CCCCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCCc1cc(-c2ccccc2)no1
Temperature: 50 °C

Procedure:
N-Hydroxybenzenecarboximidoyl chloride (prepared as described in Part A of Example 2, 2.61 g, 16.8 mmol) was added to a solution of 4-chloro-2-(ethoxymethyl)-1-pent-4-ynyl-1H-imidazo[4,5-c]quinoline (prepared as described in Part F of Example 6, 2.90 g, 8.39 mmol) and triethylamine (3.50 mL, 25.2 mmol) in dichloromethane at 6° C. The solution was heated at 50° C. under a nitrogen atmosphere for 4 hours. The solution was diluted with dichloromethane, transferred to a separatory funnel, washed with water and brine, dried over sodium sulfate, filtered, and concentrated to an oil. The oil was triturated with hexanes and the solvent was decanted. The oil was triturated with diethyl ether and a solid formed that was isolated by filtration to provide 4-chloro-2-(ethoxymethyl)-1-[3-(3-phenylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinoline (1.98 g). The filtrate was purified by flash chromatography (silica gel, gradient elution from 7:3 to 1:1 hexanes/ethyl acetate) to provide an additional 0.24 g of product. The total amount of 4-chloro-2-(ethoxymethyl)-1-[3-(3-phenylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinoline isolated was 2.22 g.
Reaction SMILES: [CH3:1][C:2](=[N:6][OH:7])[C:3](=[O:5])[CH3:4].C(N(CC)CC)C.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17].O>CCOCC>[C:15]([OH:19])(=[O:5])[C:16]([CH3:18])=[CH2:17].[N:6](=[C:2]([CH3:1])[C:3](=[O:5])[CH3:4])[OH:7]
Reactant: C=C(C)C(=O)Cl
Agent: CC(=O)C(C)=NO
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)O

Procedure:
The monomer 3-oximino-2-butanone methacrylate (OBM) was prepared. This preparation began by cooling to a temperature of 0 degree C. with an ice water bath, a solution of butanedione monoxime (54.5 g) and triethylamine (120 ml) in ether (1000 ml). Approximately 56 ml of methacryloyl chloride in 250 ml of ether was added dropwise under a nitrogen atmosphere over the course of 1 hour. The solution was stirred during this addition and the stirring was continued under nitrogen at 0 degree C. for 3 hours after the addition was completed. The resulting mixture was filtered to remove the solid residues. The solid residues were discarded, and the liquid obtained was transferred to a separatory funnel. Approximately 300 ml of water was added to the separatory funnel and the liquid was agitated. The water and ether phases were separated, the water phase was discarded, and the ether phase was dried over magnesium sulfate for 1 hour. The magnesium sulfate was removed by filtration and the ether solution was evaporated to dryness on a rotary evaporator using water aspirator vacuum. The resulting solid was recrystallized from cyclohexane to yield 45 g of OBM. (The material obtained melted between 38.5 and 39 degrees C.)
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)[C:9]2[C:10](=[O:19])[NH:11][C:12]3[C:17]=2[C:16]=1[C:15]([F:18])=[CH:14][CH:13]=3.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>C(Cl)Cl>[F:18][C:15]1[C:16]2[C:17]3[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])[C:9]=3[C:8]([C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[CH:7][C:6]=2[NH:5][CH2:4][CH2:3][NH:2][C:25](=[O:27])[CH3:26]
Reactant: NCCNc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCNc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Reaction time: 2 h

Procedure:
To a suspension of 5-(2-amino-ethylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one hydrochloride salt (from Example 10 above) (35.5 mg, 0.1 mmol) in CH2Cl2 (2 mL) were added acetic anhydride (Fisher Scientific, 10.2 mg, 0.1 mmol) and triethylamine (Aldrich, 20.2 mg, 0.2 mmol) at room temperature. The reaction mixture was stirred for 2 hours at the same temperature and then quenched with a saturated aqueous ammonium chloride solution (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were successively washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with ethyl acetate and hexanes, filtered, and dried to give N-[2-[6-fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylamino]-ethyl]-acetamide as a brown solid. (Yield 13.5 mg, 38.4%).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29](=[O:38])[C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH:23]=2)[N:9]=1.[H-].[Na+].I[CH3:51]>CN(C=O)C.C(OCC)(=O)C.O>[F:47][C:2]([F:1])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:51])[C:29](=[O:38])[C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH:23]=2)[N:9]=1
Reactant: O=C(Nc1cccc(Cn2nc(CCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n(Cc3ccccc3)c2=O)c1)c1ccc(Cl)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccc(Cl)c(Cl)c1)c1cccc(Cn2nc(CCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n(Cc3ccccc3)c2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound of Example 12 (0.187 g, 0.27 mmol) was dissolved in DMF (10 ml) and sodium hydride (0.016 g, 0.40 mmol) was added followed by iodomethane (0.025 ml, 0.40 mmol). The solution was stirred at 25° C. for 16 hours and diluted with ethyl acetate (30 ml) and water (20 ml). The organic layer was collected and washed with water (3×50 ml), dried (MgSO4) and filtered and the solvent evaporated. The residue was chromatographed on silica eluting with 30% ethyl acetate/hexanes to yield the title compound as a colourless oil. (84%).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=O)[C:9]2=O)=[CH:5][CH:4]=1)[CH3:2].[NH2:14]/[C:15](/[C:20]#[N:21])=[C:16](\[NH2:19])/[C:17]#[N:18].CC([OH:25])C>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:25])[C:8]3[C:9]([C:10]=2[CH:11]=1)=[N:14][C:15]([C:20]#[N:21])=[C:16]([C:17]#[N:18])[N:19]=3)[CH3:2]
Reactant: CC(C)O
Reactant: N#C/C(N)=C(/N)C#N
Reactant: CCc1ccc2c(c1)C(=O)C(=O)C2
Product: CCc1ccc2c(c1)-c1nc(C#N)c(C#N)nc1C2=O
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A suspension of 29c (298 mg, 1.71 mmol) and diaminomaleonitrile (185 mg, 1.71 mmol) in iPrOH (17 ml) was stirred at 80° C. for 20 h. The solvent was evaporated under reduced pressure and the crude was purified by flash chromatography (CH2Cl2). The obtained product was purified by preparative HPLC, obtaining 32 as yellow solid as 7:3 regioisomeric mixture with the 7-ethyl analogue. 1H NMR (300 MHz, CDCl3): main product: δ 7.95 (d, 1H), 7.80 (m, 1H), 7.67 (bd, 1H), 2.83 (q, 2H), 1.33 (t, 3H); minority product: δ 7.89 (d, 1H), 7.89 (m, 1H), 7.56 (bd, 1H), 2.86 (q, 2H), 1.36 (t, 3H). ESI+MS: calcd for C15H8N4O: 260.26; found: 261.1 (MH+).
Reaction SMILES: [CH:1]1[C:6]([N+]([O-])=O)=[CH:5][CH:4]=[C:3]([Cl-]C([O-])=O)[CH:2]=1.Cl.[Cl:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].CCN(C(C)C)C(C)C.[OH:34][CH2:35][C@@H:36]([NH:51][CH3:52])[CH2:37][CH2:38][CH2:39][N:40]1[C:48](=[O:49])C2C(=CC=CC=2)[C:41]1=[O:50].C1C[O:56][CH2:55]C1>>[Cl:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:55](=[O:56])[N:51]([C@@H:36]([CH2:37][CH2:38][CH2:39][N:40]1[C:41](=[O:50])[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:48]1=[O:49])[CH2:35][OH:34])[CH3:52]
Reactant: NCc1cccc(F)c1Cl
Reactant: CN[C@H](CO)CCCN1C(=O)c2ccccc2C1=O
Reactant: C1CCOC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](CO)CCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 47 %

Procedure:
To a solution of 4-nitrophenylchloroformate (460 mg, 2.29 mmol) in THF (20 mL) was added 2-chloro-3-fluorobenzylamine hydrochloride (626 mg, 2.29 mmol) and DIEA (0.76 mL, 4.58 mmol) and the mixture was stirred at RT until TLC showed complete consumption of 2-chloro-3-fluorobenzylamine. The mixture was then added into a solution of (S)-2-(5-hydroxy-4-(methylamino)pentyl)isoindoline-1,3-dione (500 mg, 1.91 mmol) in THF (10 mL). The mixture was stirred overnight, concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-3-(2-chloro-3-fluorobenzyl)-1-(5-(1,3-dioxoisoindolin-2-yl)-1-hydroxypentan-2-yl)-1-methylurea (401 mg, 47%). LRMS (M+H+) m/z 448.3.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([S:15][CH:16]1[N:19]([CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[C:18](=[O:34])[CH2:17]1)([CH3:14])([CH3:13])[CH3:12].[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].C(O)(=O)C>C1COCC1.C1(C)C=CC=CC=1>[C:11]([S:15][CH:16]1[N:19]([CH:20]([C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)=[O:22])[C:18](=[O:34])[CH2:17]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)SC1CC(=O)N1CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
6 ml of a freshly prepared 1M solution of lithium bis-trimethysilylamide in THF are added dropwise to a solution of 1059 mg (3 mmol) of p-nitrobenzyl (4-tert-butylthio-2-oxo-1-azetidinyl)acetate in 7 ml of dry THF at -70° C., and a solution of 382 mg of pivaloyl chloride in 1 ml of THF is subsequently added dropwise at -70° C., and the reaction mixture is then stirred for 30 minutes at the same temperature. The mixture is diluted with 200 ml of toluene and a little aqueous acetic acid is added. The organic phase is washed with 100 ml of 2N aqueous hydrochloric acid and twice with saturated sodium chloride solution (100 ml), the organic phase is dried using MgSO4, and the solvent is evaporated in vacuo to give a dark red oil. Purification of the crude product over 40 g of silica gel using toluene: ethyl acetate (9:1) gives 795 mg of a non-crystalline solid. IR spectrum in methylene chloride: 2970, 1770, 1760, 1715, 1610, 1530, 1370, 1350, 1315, 1180, 995, 845 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[C:15]3[CH2:16][NH:17][CH2:18][CH2:19][C:14]=3[NH:13][C:12](=[O:20])[N:11]2[CH:21]=1.[CH:22](=O)[CH2:23][CH2:24][CH3:25].C([BH3-])#N.[Na+].Cl>O.CO>[CH2:22]([N:17]1[CH2:18][CH2:19][C:14]2[NH:13][C:12](=[O:20])[N:11]3[CH:21]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:9]=[C:10]3[C:15]=2[CH2:16]1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCC=O
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CNCC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCN1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Reaction time: 6 h

Procedure:
To 2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (171 mg, 0.6 mmol) in pH4-5 HCL-methanol (6 mL) at room temperature was added n-butyraldehyde (53 uL, 0.6 mmol) and sodium cyanoborohydride (38 mg, 0.6 mmol). After the reaction mixture was stirred for 6 hours, concentrated HCl was added until the mixture became homogenous. The mixture was then diluted with water (5 mL) and extracted twice with ether. The aqueous layer was made alkaline with aqueous ammonium hydroxide, saturated with sodium chloride, and extracted twice with 10% methanol/ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give 9-n-Butyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (Compound 48). Recrystallization from aqueous ethanol gave a white fluffy solid, m.p. 251°-253° C. (d).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C.C1(C)C=CC=CC=1>CCCCCC>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:3]=1[NH:4][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1cc(C(F)(F)F)ccc1Cl)C(=O)OCC
Temperature: 140 °C

Procedure:
2-Chloro-5-(trifluoromethyl)aniline (2) (200 g, 1.023 mol), diethyl 2-(ethoxymethylene)malonate (3) (276 g, 1.3 mol) and toluene (100 mL) were combined under a nitrogen atmosphere in a 3-neck, 1-L round bottom flask equipped with Dean-Stark condenser. The solution was heated with stirring to 140° C. and the temperature was maintained for 4 hours (h). The reaction mixture was cooled to 70° C. and hexane (600 mL) was slowly added. The resulting slurry was stirred and allowed to warm to room temperature. The solid was collected by filtration, washed with 10% ethyl acetate in hexane (2×400 mL) and then dried under vacuum to provide the product, diethyl 2-((2-chloro-5-(trifluoromethyl)phenylamino)methylene)malonate (4), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.28 (d, J=13.0 Hz, 1H), 8.63 (d, J=13.0 Hz, 1H), 8.10 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.50 (dd, J=1.5, 8.4 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 4.17 (q, J=7.1 Hz,2 H), 1.27 (m, 6H).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:8]=1)=O.[C:27]1([NH:33]N)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO>[C:27]1([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([N:20]5[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]5)=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(N3CCCCC3)cc2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: O=c1ccn(-c2ccc(N3CCCCC3)cc2)nc1-c1ccnn1-c1ccccc1
Yield: 4 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-piperidin-1-ylphenyl)pyridazin-4(1H)-one (crude 700 mg, 1.99 mmol) in 20 mL of methanol was added phenylhydrazine (858 mg, 7.94 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 3-(1-phenyl-1H-pyrazol-5-yl)-1-(4-piperidin-1-ylphenyl)pyridazin-4(1H)-one (30 mg, 4% for two steps) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[C:24]1([CH:34]=O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)Cl>ClCCCl.C1COCC1>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([NH:13][C:14](=[O:22])[C:15]1[CH:16]=[CH:17][C:18]([NH:21][CH2:34][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:20]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([Br:12])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1ccc(N)cc1
Reactant: O=Cc1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1ccc(NCc2cccc3ccccc23)cc1
Yield: 48 %

Procedure:
(S)-3-(4-Bromo-phenyl)-2-{4-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-propionic acid methyl ester (273 mg) was prepared from (S)-2-(4-amino-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (415 mg, 1.1 mmol) and 1-naphthaldehyde (0.331 mL, 2.4 mmol) according to Procedure G, except for the following: the reaction was done in 15 mL DCE and 5 mL THF, was allowed to stir for 15 min before NaBH(OAc)3was added, was treated with two additional equiv. NaBH(OAc)3 after 2 h, and an adapted work-up. After reaction completion, 100 mL of DCM was added and the organic washed with saturated sodium bicarbonate, dried over sodium sulfate, and evaporated. The crude material was triturated with MeOH.
Reaction SMILES: [C:1]([C:3]1([NH:9][C:10](=[O:40])[C@@H:11]([NH:20][C@@H:21]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:22]([F:32])([F:31])[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:12][S:13]([CH2:16][CH:17]2[CH2:19][CH2:18]2)(=[O:15])=[O:14])[CH2:8][CH2:7]S[CH2:5][CH2:4]1)#[N:2].OO[S:43]([O-:45])=[O:44].[K+]>CO.O>[C:1]([C:3]1([NH:9][C:10](=[O:40])[C@@H:11]([NH:20][C@@H:21]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:22]([F:32])([F:31])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:12][S:13]([CH2:16][CH:17]2[CH2:19][CH2:18]2)(=[O:15])=[O:14])[CH2:4][CH2:5][S:43](=[O:45])(=[O:44])[CH2:7][CH2:8]1)#[N:2]
Reactant: O=S([O-])OO
Reactant: N#CC1(NC(=O)[C@H](CS(=O)(=O)CC2CC2)N[C@@H](c2ccc(F)cc2)C(F)(F)Oc2ccc(F)cc2)CCSCC1
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#CC1(NC(=O)[C@H](CS(=O)(=O)CC2CC2)N[C@@H](c2ccc(F)cc2)C(F)(F)Oc2ccc(F)cc2)CCS(=O)(=O)CC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of N-(4-cyanotetrahydrothiopyran-4-yl)-3-cyclopropylmethanesulfonyl-2(R)-[2,2-difluoro-2-(4-fluorophenoxy)-1(S)-(4-fluorophenyl)ethylamino]propionamide (0.063 g, 0.1 mmol) in MeOH (10 ml) at 45° C., a solution of OXONE (0.3 mmol) in water (1 ml) was added. After stirring for 3 h at 45° C., the solvent was evaporated under vacuum and the residue was partitioned between DCM (15 ml) and water (15 ml). The organic phase was separated and the aqueous solution was extracted with DCM. The combined organic layers were washed with brine and dried over sodium sulfate. After removal of the solvent under vacuum, the crude was purified by preparative TLC, using ethyl acetate/hexanes (1/1) as mobile phase to give the title compound as a white solid (55%). 1HNMR (DMSO-d6): δ 8.82 (1H, s), 7.47 (2H, dd), 7.17 (6H, m), 4.32 (1H, q), 3.96 (1H, m), 3.40 (1H, m), 3.37 (4H, m), 3.00 (2H, m), 2.37 (2H), 1.15 (2H, m), 0.59 (3H, m), 0.30 (3H, m). LC/MS, M+1: 632.5; M−1: 630.6.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[Cl:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:23]=1[C:24]([NH:2][CH2:3][C:4](=[O:5])[NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:25]
Reactant: O=C(O)c1ccc(F)cc1Cl
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(F)cc1Cl)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 2-chloro-4-fluorobenzoic acid.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH:12]1(CBr)[CH2:16][CH2:15][CH2:14][CH2:13]1.[C:19](=O)([O-])[O-:20].[K+].[K+]>CN(C)C=O>[CH:12]1([C:2]2[C:3]([O:20][CH3:19])=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrCC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c(OC)c1C1CCCC1
Temperature: 60 °C
Yield: 73.5 %

Procedure:
A stirred solution of 3-hydroxy-4-methoxy-benzaldehyde (5.74 g) in dry dimethylformamide (50 mL) is treated with cyclopentylmethyl bromide (7.34 g) and potassium carbonate (15 g), and the solution is heated at 60° C. for 24 hours. After cooling and filtration, the solution is evaporated to low bulk and dissolved in ethyl acetate (100 mL). The organic solution is washed with aqueous sodium hydroxide solution (4×50 mL; 2 N) and water (2×50 mL), dried over magnesium sulfate, and evaporated to give 3-cyclopentyl-methoxy-4-methoxybenzaldehyde (6.5 g) in the form of a light brown oil.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Na].[C:15]([C:19]1[CH:27]=[CH:26][C:22]([CH:23](Cl)[CH3:24])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH:23]([CH3:24])[C:22]2[CH:26]=[CH:27][C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: CC(Cl)c1ccc(C(C)(C)C)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(Sc1cnn(C(C)(C)C)c(=O)c1Cl)c1ccc(C(C)(C)C)cc1
Yield: 72.7 %

Procedure:
By conducting a procedure similar to that in Synthesis Example 3 except using 1.5 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone, 10 ml of N,N-dimethylformamide, 1.0 g of anhydrous sodium carbonte and 1.4 g of 4-tert.-butyl-α-methylbenzyl chloride, there were obtained white needle-like crystals having the following physical properties (yield: 72.7%):