Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:4][C:3]=1[C:16]([F:19])([F:18])[F:17].C(N(C(C)C)CC)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[Cl:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[CH2:78][SH:79]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[CH2:78][S:79][C:2]1[S:6][C:5]([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:4][C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: SCc1ccccc1Cl
Reactant: O=C(Nc1nc(C(F)(F)F)c(Br)s1)c1ccccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc(C(F)(F)F)c(SCc2ccccc2Cl)s1)c1ccccn1
Temperature: 100 °C

Procedure:
In a 5 mL microwave vial was charged with N-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)picolinamide (0.06 g, 0.2 mmol), diisopropylethylamine (59 μL, 0.34 mmol), Pd2(dba)3 (0.0048 g, 0.0085 mmol), Xantphos (0.0099 g, 0.017 mmol), 1,4-dioxane (0.6 mL) and 2-chlorophenylmethanethiol (22 μL, 0.17 mmol). The reaction mixture was purged with argon for 5 min; the vial was capped and heated at 100° C. for 15 h. the reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), filtered, washing with ethyl acetate (10 mL) and the filtrate was concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/hexanes 0 to 30% to give the product.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)#[N:2].[CH:18]1([NH2:21])[CH2:20][CH2:19]1>C(O)C>[C:1]([N:3]=[C:4]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[NH:21][CH:18]1[CH2:20][CH2:19]1)#[N:2]
Reactant: CSC(=NC#N)NC1CCCc2ccccc21
Reactant: NC1CC1
Solvent: CCO
Product: N#CN=C(NC1CC1)NC1CCCc2ccccc21
Reaction time: 120 h

Procedure:
A solution of 24.6 g of N'-cyano-N-(1,2,3,4-tetrahydro-1-naphthyl)-S-methylisothiourea and 25.0 g of cyclopropylamine in 250 ml of ethanol was heated at reflux with stirring for ca. 120 hours. The solvent was then removed by evaporation in vacuo. The residual oil was dissolved in a mixture of hot isopropyl acetate and ethanol, and the solution was allowed to stand in the refrigerator overnight to give the partially-purified product as a white, crystalline solid. A further quantity of the crude product was obtained by the concentration and subsequent cooling of the mother liquor. Recrystallization from isopropyl acetate, containing a small amount of ethanol, gave N"-cyano-N-cyclopropyl-N'-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as 7.75 g of a white, crystalline solid, mp 170.5°-171.5° C.
Reaction SMILES: C[Mg]Cl.[CH3:4][C:5](=[CH:7][CH2:8][CH2:9]/[C:10](=[CH:12]/[CH:13]=[O:14])/[CH3:11])[CH3:6].[NH4+].[Cl-].[CH3:17]CCCCC>COC(C)(C)C.O>[CH3:11][C:10]([CH2:9][CH2:8][CH:7]=[C:5]([CH3:4])[CH3:6])=[CH:12][CH:13]([OH:14])[CH3:17]
Reactant: CC(C)=CCC/C(C)=C/C=O
Reactant: CCCCCC
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)=CCCC(C)=CC(C)O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
1 l of t-butyl methyl ether and 1.05 l of 3N methyl magnesium chloride solution were placed under N2 in a 41/2 l sulphonation flask having a thermometer, stirrer and dropping funnel and 456 g of geranial in 500 ml of t-butyl methyl ether were added dropwise at 0° C. The mixture was stirred at 10° C. for 1 hour and poured on to 3 kg of ice and 500 g of NH4Cl and treated with 1 l of hexane. After mixing well the H2O phase was separated and washed neutral 3 times with 500 ml of NH4Cl solution, dried and evaporated.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:17]=2[N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:36])[CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:21][CH2:20]2)[NH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][CH2:27][CH2:26][C:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17]2[C:16]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:15][N:14]=[C:13]3[NH:12][CH:11]=[C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=4)[C:18]=23)[CH2:20][CH2:21]1)=[O:36]
Reactant: CC(C)(C)OC(=O)NCCC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
tert-Butyl 3-(4-(3-(nicotinamido)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate (0.020 g, 0.035 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.5 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added to a stirring solution of 1M HCl in ether. The resulting solid product was filtered, washed with ether and dried to give the product N-(4-(4-(3-aminopropanoyl)piperazin-1-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.008 g, 39% yield) as the trihydrochloride salt. MS APCI (+) m/z 470 detected.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1F)[C:14]#[N:15]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][C:18]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[Cl:10]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: Nc1ccc(Cl)cc1O
Product: N#Cc1ccc(Oc2cc(Cl)ccc2N)c(Cl)c1

Procedure:
The subtitle compound was prepared by the method of example 3 step viii) using 2-amino-5-chlorophenol and 3-chloro-4-fluorobenzonitrile. Yield 2.70 g
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][C@@H:11]2[C@@H:27]([CH3:28])[C:26](=[O:29])[O:25][C@H:24]([CH2:30][CH3:31])[C@:23]3([CH3:32])[C@H:19]([NH:20][C:21](=[O:33])[O:22]3)[C@@H:18]([CH3:34])[C:17](=[O:35])[C@H:16]([CH3:36])[CH2:15][C@:14]([O:38][C:39]([NH2:41])=[O:40])([CH3:37])[C@H:13]([O:42][C@@H:43]3[O:52][C@H:51]([CH3:53])[CH2:50][C@H:49]([N:54]([CH3:56])[CH3:55])[C@H:44]3[O:45][C:46](=[O:48])[CH3:47])[C@H:12]2[CH3:57])=[O:9])[CH:2]=1.[CH:58]([CH:60]([CH2:63][CH:64](OC)OC)[C:61]#[N:62])=O.FC(F)(F)C(O)=O>CC#N.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][C@@H:11]2[C@@H:27]([CH3:28])[C:26](=[O:29])[O:25][C@H:24]([CH2:30][CH3:31])[C@:23]3([CH3:32])[C@H:19]([NH:20][C:21](=[O:33])[O:22]3)[C@@H:18]([CH3:34])[C:17](=[O:35])[C@H:16]([CH3:36])[CH2:15][C@:14]([O:38][C:39]([N:41]3[CH:64]=[CH:63][C:60]([C:61]#[N:62])=[CH:58]3)=[O:40])([CH3:37])[C@H:13]([O:42][C@@H:43]3[O:52][C@H:51]([CH3:53])[CH2:50][C@H:49]([N:54]([CH3:55])[CH3:56])[C@H:44]3[O:45][C:46](=[O:48])[CH3:47])[C@H:12]2[CH3:57])=[O:9])[CH:2]=1
Reactant: COC(CC(C#N)C=O)OC
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](OC(=O)Cc2cccnc2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2OC(C)=O)[C@](C)(OC(N)=O)C[C@@H](C)C(=O)[C@H](C)[C@H]2NC(=O)O[C@@]21C
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](OC(=O)Cc2cccnc2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2OC(C)=O)[C@](C)(OC(=O)n2ccc(C#N)c2)C[C@@H](C)C(=O)[C@H](C)[C@H]2NC(=O)O[C@@]21C
Temperature: 60 °C
Yield: 41.8 %

Procedure:
To a mixture of compound of Example 34 (0.35 g, 0.435 mmol) and 2-formyl-4,4-dimethoxy-butyronitrile (0.30 g, 1.91 mmol) in CH3CN was added trifluoroacetic acid (0.33 mL, 4.35 mmol). The mixture was heated to 60° C. for 18 hours and additional 2-formyl-4,4-dimethoxy-butyronitrile (0.15 g, 0.186 mmol) and trifluoroacetic acid (0.15 mL, 1.95 mmol) were added. The mixture is was heated to 60° C. for 18 hours before being cooled, diluted with ethyl acetate, washed with sat. aq. NaHCO3, water, brine, and dried over MgSO4. Concentration and chromatography (silica gel, 98:2:0.3 dichloromethane/methanol/conc. NH4OH) gave 0.16 g (41%) of the title compound. MS 880 (M+H)+.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].Cl[CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:20]=1.OCCCN.ClCC1C=NC=C(C2C=CC(F)=CC=2)C=1.P(Cl)(Cl)Cl>C(#N)C>[O:7]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH:20]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1ccc(-c2cncc(CNCCCCl)c2)cc1
Reactant: [O-]c1ccccc1
Agent: Fc1ccc(-c2cncc(CCl)c2)cc1
Agent: NCCCO
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: CC#N
Product: Fc1ccc(-c2cncc(CNCCCOc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Analogously to Example 7 a solution of 2.3 g sodium phenolate and 2.5 g N-3-chloropropyl-N-[5-(4-fluorophenyl)-3-pyridylmethyl]-amine [obtainable by reaction of 3-hydroxypropylamine with 3-chloromethyl-5-(4-fluorophenyl)-pyridine and subsequent transformation of the product to the 3-chloropropyl-compound by reaction with PCl3 ] in 200 ml of acetonitrile is stirred for 5 hours at room temperature and worked up in a conventional manner to give N-(3-phenoxy-propyl)-N-[5-(4-fluorophenyl)-3-pyridyl-methyl]-amine. Stirring with Q5 equivalents of oxalic acid in 100 ml ethanol/water mixture gives the oxalate-hemihydrate, m.p. 217°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:36][O:37][C:38]([C:40]1[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=1[NH2:42])=[O:39]>CN(C=O)C>[CH3:36][O:37][C:38]([C:40]1[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=1[NH:42][C:16](=[O:18])[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:39]
Reactant: COc1ccc(C(=O)N2CCN(CC(=O)O)CC2)cc1
Reactant: COC(=O)c1ccccc1N
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)CN1CCN(C(=O)c2ccc(OC)cc2)CC1

Procedure:
2.5 Grams of [4-(4-methoxybenzoyl)-1-piperazinyl]acetic acid was dissolved in 30 ml of DMF, then 1.2 g of triethylamine was added thereto. Under an ice-cooled condition with stirring, 1.4 g of isobutyl chloroformate was added dropwise thereto and stirred for 30 minutes. Then, the reaction mixture was stirred at a room temperature, a DMF solution of 1.6 g of o-methoxycarbonylaniline was added dropwise to the reaction mixture and stirred for 6 hours. The reaction mixture obtained was concentrated to dryness, and the residue obtained was extracted with chloroform and 1 N-sodium hydroxide. The chloroform layer was washed with water, dried and then chloroform was removed by distillation. The residue obtained was crystallized by adding ethyl acetate, the crystals formed were collected by filtration. Recrystallized from ethanol to obtain 2.1 g of o-methoxycarbonyl-α-[4-(4-methoxybenzoyl)-1-piperazinyl]acetanilide in the form of colorless needle-like crystals. Melting point: 167.5°-169.0° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[Cl:10].S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>>[Cl:10][C:3]1[C:2]([F:1])=[C:7]([F:8])[C:6]([F:9])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: Fc1ccc(Cl)c(F)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(F)c(F)c(F)c1Cl

Procedure:
If 0.15 mol of 2,3,4-trifluorochlorobenzene in 50 g of 100% strength sulfuric acid as diluent is used and nitration is carried out with 30.5 g (0.165 mol) of mixed acid prepared from 68.8% by weight of 100% strength H2SO4 and 31.2% by weight of 100% strength HNO3 at from 5° to 12° C., then reaction is complete after metered addition for 1 hour followed by stirring for an additional hour. The result is essentially the same.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH3:13][Mg]Cl>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([OH:12])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: O=C1CCCc2nc(Cl)ccc21
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC1(O)CCCc2nc(Cl)ccc21

Procedure:
To a solution of 2-chloro-7,8-dihydroquinolin-5(6H)-one (500 mg, 2.75 mmol) in tetrahydrofuran (20 mL) at 0° C. was added methylmagnesium chloride (3.0 M in tetrahydrofuran, 0.92 ml, 2.8 mmol) over 2 minutes dropwise. Additional methylmagnesium chloride (3.0 M in tetrahydrofuran) were added at the following time intervals after the initial addition: 40 minutes (0.46 ml, 1.4 mmol); 60 minutes (0.46 ml, 1.4 mmol); and 120 minutes (0.92 ml, 2.8 mmol). At 1 hour after the final addition, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL), and diluted with ethyl acetate (30 mL). The organic layer was separated and washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (10-50% ethyl acetate/hexanes, linear gradient) to give 2-chloro-5-methyl-5,6,7,8-tetrahydroquinolin-5-ol. MS ESI calc'd. for C10H13ClNO [M+H]+ 198. found 198.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]1([S:17][CH2:18][C:19]([NH:21][C:22]2[C:31]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=3)=[C:25]3[N:26]=[CH:27][C:28]([CH3:30])=[CH:29][N:24]3[N:23]=2)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[CH:12]1([S:17]([CH2:18][C:19]([NH:21][C:22]2[C:31]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=3)=[C:25]3[N:26]=[CH:27][C:28]([CH3:30])=[CH:29][N:24]3[N:23]=2)=[O:20])=[O:6])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1cnc2c(-c3ccc(F)c(C)c3)c(NC(=O)CSC3CCCC3)nn2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cnc2c(-c3ccc(F)c(C)c3)c(NC(=O)CS(=O)C3CCCC3)nn2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Solid m-chloroperoxybenzoic acid (30 mg, about 50% titre, 0.10 mmol) was added to an ice-cooled solution of the product from Example 143D (37 mg, 0.093 mmol) in CHCl3 (7 mL). The yellow solution was stirred with ice cooling for 15 minutes, then transferred to a test tube and washed with 20% Na2CO3 (4 mL). The organic phase was concentrated under vacuum, and the residue purified by HPLC (30×100 mm XBridge column eluted with aqueous 0.1 M (NH4)2CO3-MeOH, 80:20-0:100 over 15 min), then by flash chromatography (silica gel eluted with EtOAc-MeOH, 100:0-80:20) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.38-1.54 (m, 1H), 1.64-1.86 (m, 4H), 1.90-2.23 (m, 3H), 2.30 (d, J=1.6 Hz, 3H), 2.38 (s, 3H), 3.34-3.49 (m, 2H), 3.88 (d, J=14.3 Hz, 1H), 7.22-7.31 (m, 1H), 7.34-7.48 (m, 2H), 8.39 (s, 1H), 8.42-8.55 (m, 1H), 9.51 (s, 1H); MS (ESI) m/z 415 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:23])[CH2:19][CH:20]2[CH2:22][CH2:21]2)=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:23])[CH2:19][CH:20]2[CH2:21][CH2:22]2)=[CH:16][CH:17]=1
Reactant: OC(CC1CC1)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CC1CC1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Oxalyl chloride (14.3 ml, 160 mmol) was added dropwise to a stirred solution of dimethylsulphoxide (14.3 ml, 200 mmol) in dry dichloromethane (350 ml) at -78° C. After 15 minutes 1-(4-chlorophenyl)-2-cyclopropylethanol (12.98 g, 66 mmol) in dry dichloromethane (120 ml) was added to the mixture. After an hour triethylamine (71.4 ml), 510 mmol) was added and the mixture warmed to room temperature and poured into water. The mixture was extracted with dichloromethane and the combined extracts washed with water, dried and evaporated in vacuo to give crude 1-(4-chlorophenyl)-2-cyclopropylethanone which was used without further purification.
Reaction SMILES: CC1C=CC=C(C)C=1C[N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[CH:6]1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:32]=1[CH2:33]Cl.[OH-].[Na+]>CN1CCCC1=O.O1CCCC1.CO>[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:32]=1[CH2:33][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[CH:6]1
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: Cc1cccc(C)c1Cn1cc(C)c2ccc(CC(=O)O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1cn(Cc2c(Cl)cccc2Cl)c2cc(CC(=O)O)ccc12
Yield: 63 %

Procedure:
To a solution of the compound obtained in the process (3) of Example 64 [64-3] (272 mg) in N-methyl-2-pyrrolidone (4 mL) were added potassium carbonate (555 mg) and 2,6-dichlorobenzyl chloride (516 mg) at room temperature, and then the reaction mixture was subjected to microwave irradiation at 130° C. for 40 minutes. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give a brown oil. The obtained oil was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL). 3N-sodium hydroxide (1 mL) was added at room temperature, and then the reaction mixture was subjected to microwave irradiation at 160° C. for 10 minutes. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (194 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:14](OC)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:14][OH:15])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: OCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 104.3 %

Procedure:
A stirred solution of 76.1 g of methyl 1-benzyl-4-anilino-4-piperidine carboxylate in 1200 ml of toluene is maintained at ambient temperature while 130 ml of a 70% solution of sodium dihydrobis(2-methoxyethoxy)aluminate in benzene is added dropwise. Stirring is continued for one hour after the addition. Two hundred grams of a saturated solution of sodium sulfate is added. The aqueous portion is removed and the organic portion is dried over sodium sulfate and flash evaporated to give 72.5 g of 1-benzyl-4-anilino-4-piperidinemethanol, as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[C:10]1[CH2:9][CH2:8][CH:7]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH2:6][C:5]2=1.[CH3:29][NH:30][CH3:31].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[Fe+2]>[CH3:29][N:30]([CH3:31])[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[C:10]1[CH2:9][CH2:8][CH:7]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH2:6][C:5]2=1
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(Br)ccc3n2Cc2cccc(F)c2)C1
Reactant: CNC
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)C(=O)NC1CCc2c(c3cc(N(C)C)ccc3n2Cc2cccc(F)c2)C1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
In a sealed tube, heat N-[6-bromo-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (Example 35) (200 mg, 0.45 mmol), dimethyl amine (2.0 M in tetrahydrofuran, 0.45 mL, 0.90 mmol), palladium acetate (5 mg, 0.002 mmol), sodium tert-butoxide (133 mg, 1.38 mmol), and 1,2,3,4,5-pentaphenyl-1′-(di-t-butylphosphino)ferrocene ligand (60 mg, 0.008 mmol) in toluene (5 mL) at 70° C. overnight. Cool to room temperature, dilute with ethyl acetate/10% potassium carbonate, and filter off the red suspension. Wash the organic portion with 10% aqueous potassium carbonate (2×), dry over anhydrous sodium sulfate, filter, and concentrate. Purify the residue by silica gel column chromatography eluting with 40 to 100% ethyl acetate/hexanes to obtain the title compound (135 mg, 74%). MS (ES): m/z 408 (M+1); 1H NMR (CD3OD): δ 7.25 (m, 1H), 7.18 (d, 1H), 7.01 (s, 1H), 6.96 (t, 1H), 6.89 (d, 1H), 6.81 (d, 1H), 6.65 (d, 1H), 5.30 (s, 2H), 4.19 (m, 1H), 3.08 (dd, 1H), 2.88 (s, 6H), 2.77 (m, 2H), 2.63 (m, 1H), 2.50 (m, 1H), 2.12 (m, 1H), 1.97 (m, 1H), 1.18 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](Cl)=[N:12][CH:11]=1.[CH2:18]([NH2:23])[CH2:19][CH2:20][CH2:21][NH2:22]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH:22][CH2:21][CH2:20][CH2:19][CH2:18][NH2:23])=[N:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(Cl)nc1
Reactant: NCCCCN
Product: NCCCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Yield: 53 %

Procedure:
N-(2-Aminophenyl)-6-chloronicotinamide (248 mg, 1 mmol) and 7 ml of 1,4-butanediamine were heated to 80° C. for 3 hours. The excess 1,4-butanediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (158 mg, 53% yield) as a brown solid. LC-MS (m/z) 300 (M+1).
Reaction SMILES: [NH2:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[NH:4][C:3]1=[O:14].[CH2:22]([N:24]([CH2:38][CH3:39])[C:25](=[O:37])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[CH3:23]>>[NH2:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[N:4]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:25]([N:24]([CH2:38][CH3:39])[CH2:22][CH3:23])=[O:37])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[C:3]1=[O:14]
Reactant: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2S(=O)(=O)c1ccc(NC(=O)N(CC)CC)cc1

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 30 from 3-amino-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one and 4-(N',N'-diethylureido)benzenesulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[C:8]([O:9]C)=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].B(Br)(Br)Br>ClCCl>[NH2:4][C:3]1[C:2]([F:1])=[C:8]([OH:9])[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(N)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1cccc(O)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.9 %

Procedure:
To a stirred solution of 2-fluoro-3-methoxyaniline (3.0 g, 21.26 mmol) in dichloromethane (80 mL), at 0° C., was added a 4.0 M solution of boron tribromide in dichloromethane (10.63 mL, 42.52 mmol). The reaction mixture was allowed to warm to rt and stirring was continued for a further 15 h. The reaction mixture was quenched via the addition of methanol. After concentration under reduced pressure, the residue was taken up in water, basified with saturated sodium hydrogen carbonate solution, and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to afford 3-amino-2-fluorophenol (2.70 g, 100%) as a brown solid which was taken on without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.36 (brs, 1H), 6.62 (dd, J=8, 8 Hz, 1H), 6.12-6.23 (m, 2H), 5.14 (brs, 2H); LC-MS (ESI) m/z 128 (M+H)+.