Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:17]3[C:28](=[O:32])[NH:29][C:30](=[O:31])[C:16]=3[C:15]=2[C:14]2[CH:13]=[C:12]([OH:33])[CH:11]=[CH:10][C:9]1=2)(=O)=O.[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[C:17]2[C:28](=[O:32])[NH:29][C:30](=[O:31])[C:16]=2[C:15]2[C:14]3[CH:13]=[C:12]([OH:33])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:7][CH2:6][S:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:20]=2[CH:19]=1
Reactant: CS(=O)(=O)OCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Reactant: Sc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1c2c2cc(O)ccc2n1CCSc1ccccc1
Temperature: 110 °C
Yield: 27 %

Procedure:
Mesylate (229) (55 mg, 0.11 mmol) prepared as decribed in example 171 was reacted with excess thiophenol (0.10 mL) according to the procedure described in example 179, except that triethylamine (2.0 mL) was added and the reaction was heated at 110° C. for 4 days. Addition of water was followed by extracted of the compound with with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness followed by chromatography on silica eluting with ethyl acetate/hexane (1:4 to 1:1) to give carbazole (242) (16 mg, 27%) as an orange powder, mp 262–264° C. 1H NMR δ [(CD3)2SO] 11.04 (br s, 1H), 9.37 (br s, 1H), 8.34 (d, J=2.5 Hz, 1H), 7.58 (m, 1H), 7.46 (m, 5H), 7.19 (m, 2H), 7.12 (m, 3H), 7.05 (m, 1H), 4.66 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.4 Hz, 2H). Found: C, 63.64; H, 4.09; N, 4.98. C28H19ClN2O3S.1¾H2O requires: C, 63.39; H, 4.28; N, 5.28.
Reaction SMILES: Cl.[N:2]1[C:7]2[NH:8][CH:9]=[C:10]([C:11]3[N:16]=[C:15]([C:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=4)[CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=[N:4][CH:3]=1.[C:23]([CH2:25][C:26](ON1CCCC1)=[O:27])#[N:24].C(N(C(C)C)CC)(C)C.O>C(O)C>[O:27]=[C:26]([N:20]1[CH2:19][CH:18]=[C:17]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]3[C:6]4[CH:5]=[N:4][CH:3]=[N:2][C:7]=4[NH:8][CH:9]=3)[N:16]=2)[CH2:22][CH2:21]1)[CH2:25][C:23]#[N:24]
Reactant: N#CCC(=O)ON1CCCC1
Reactant: C1=C(c2cccc(-c3c[nH]c4ncncc34)n2)CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCO
Product: N#CCC(=O)N1CC=C(c2cccc(-c3c[nH]c4ncncc34)n2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 16.1 %

Procedure:
As shown in FIG. 7—step v, compound 29 (30 mg) and 2-cyano acetic acid, pyrrolidin-1-yl ester (47 mg) were mixed in ethanol (2 mL) and diisopropylethylamine (0.084 mL) was added. After stirring at rt for 12 hours, water (30 mL) was added. Extraction with dichloromethane (3×) and chromatographic purification (SiO2, ethyl acetate) afforded 5.3 mg of 3-oxo-3-[6-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-yl]-propionitrile (compound 30).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH:12]=1)[O:7][CH2:8][C:9]([OH:11])=O.Cl.CN(C)CCCN=C=NCC.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH:12]=1)[O:7][CH2:8][C:9]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:11]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1OCC(=O)O
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1OCC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-acetic acid (0.051 g, 0.10 mmol) in methylene chloride (1 mL) was added 4-dimethylaminopyridine (0.022 g, 0.18 mmol), (3-(dimethylamino)propyl)ethyl carbodiimide hydrochloride (0.033 g, 0.17 mmol), methanesulfonamide (0.016 g, 0.17 mmol) and triethylamine (0.040 mL, 0.29 mmol). The reaction was stirred at ambient temperature for 3 days. The reaction mixture was then diluted with dichloromethane and washed with 10% aqueous acetic acid. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate and concentrated in vacuo. Chromatography on silica gel followed by trituration with methylene chloride/hydrogen chloride in diethyl ether gave the title compound as the hydrochloride salt (0.015 g, LRMS: 542.1, 544.1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][C:28](=O)[C:29]3[CH:34]=[CH:33][C:32]([CH2:35][N:36]4[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]4)=[CH:31][CH:30]=3)=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15].P(Cl)(Cl)(Cl)(Cl)Cl.C([BH3-])#N.[Na+]>N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:35][N:36]4[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]4)=[CH:33][CH:34]=3)=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)c1ccc(CN2CCS(=O)(=O)CC2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: O=c1onc(-c2nonc2NCc2ccc(CN3CCS(=O)(=O)CC3)cc2)n1-c1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 46.4 %

Procedure:
A solution of N-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzamide trifluoroacetate (20 mg, 28 μmol) in pyridine (0.5 mL) was treated with phosphorus pentachloride (18 mg, 85 μmol) and stirred at 0° C. for 4.5 h. The reaction mixture was concentrated, diluted with ethanol (1 mL), treated with sodium cyanoborohydride (5 mg, 85 μmol), and stirred for 2 h. The reaction mixture was purified by preparative LCMS to give the desired product (9 mg, 47%). LCMS for C22H21BrFN6O5S (M+H)+: m/z=579.0, 581.0.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][N:4]([NH:9]C(=O)C)[C:5](=[O:8])[NH:6][N:7]=1.Cl.Cl.[NH2:15][N:16]1[CH2:21][C:20](C)=[N:19]NC1=O.[CH3:24][OH:25]>>[NH2:9][N:4]1[CH2:3][C:2]([CH3:1])=[N:7][NH:6][C:5]1=[O:8].[NH2:15][C:16]1[C:24](=[O:25])[NH:4][N:19]=[N:20][CH:21]=1
Reactant: CO
Reactant: CC(=O)NN1CC(C)=NNC1=O
Agent: CC1=NNC(=O)N(N)C1
Agent: Cl
Product: Nc1cnn[nH]c1=O
Temperature: 45 °C
Reaction time: 2 h

Procedure:
A suspension is prepared of 39.9 g (0.234 mol) 6-methyl-4-acetylamino-4,5-dihydro-1,2,4-triazin-3-(2H)-one in 99 g 95% methanol. The suspension is heated to 45° C. and becomes a clear colourless solution. At between 45° and 50° C. a total of 15.4 g (0.421 mol) HCl are bubbled through this solution over a 2 to 3 hour period. After about 30% of the HCl has been added the reaction mixture is seeded with 4-amino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine hydrochloride. Thereafter 4-amino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine precipitates out continuously as the hydrochloride salt. After about 2 hours stirring, the maximum conversion of over 99% is reached. The reaction mixture is brought to pH 5 by the addition of 50% NaOH solution. The free aminotriazinone 4-amino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine is formed in an amount of 29.7 g representing 14.3% by weight of the solution. This represents a yield of 99.2% of theory.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=1)[C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[O:17][C:18]([CH2:21][N:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=1)=[O:10]>C(O)C>[CH3:1][NH:2][C:3](=[O:4])[NH:5][C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=1)[C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[O:17][C:18]([CH2:21][N:22]([CH3:23])[CH3:24])=[CH:19][CH:20]=1)=[O:10]
Reactant: CN=C=O
Reactant: CN(C)Cc1ccc(CSCCNC(=O)c2cccc(N)c2)o1
Solvent: CCO
Product: CNC(=O)Nc1cccc(C(=O)NCCSCc2ccc(CN(C)C)o2)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.3 g of methyl isocyanate in 10 ml of absolute ethanol is added dropwise to a solution of 6 g of 3-amino-N-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]benzamide in 50 ml of absolute ethanol. Then the mixture is left to stand 30 minutes at room temperature and afterwards it is heated at 50° C. for 2 hours. The solvent is evaporated under reduced pressure, the residue is taken up with diluted hydrochloric acid, the aqueous solution is extracted twice with 100 ml of ethyl acetate and treated with concentrated sodium hydroxide to clearly basic pH. The mixture is extracted three times with 100 ml of ethyl acetate, the organic phase is washed with water, dried on anhydrous sodium sulfate and evaporated to dryness. Thus, the 3-(3-methylureido)-N-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]benzamide is obtained as an oil which is dissolved in isopropanol and treated with a solution of 1.5 g of oxalic acid in isopropanol. A white solid is obtained which, after crystallization from 95% ethanol gives 4.5 g of 3-(3-methylureido)-N-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]benzamide oxalate; m.p. 156°-158° C. Code number: SR 57934A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH:33]1([NH2:43])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:43][CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][CH2:34]1)=[O:31]
Reactant: O=C(Br)CBr
Reactant: NC1CCCc2ccccc21
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)c(OC)c32)cc1OC
Product: COc1ccc(CC2c3c(cc(OC)c(OC)c3OC)CCN2CC(=O)NC2CCCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10](OCC)=[O:11])=O.[BH4-].[Na+].II.CO>O1CCCC1>[CH3:1][NH:2][CH2:3][CH2:5][C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][OH:11]
Reactant: CCOC(=O)COc1ccccc1CC(=O)NC
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCCc1ccccc1OCCO
Temperature: 25 °C
Yield: 28.9 %

Procedure:
At 0° C., a solution of ethyl 2-(2-((N-methylcarbamoyl)methyl)phenoxy)acetate (5.00 g, 19.9 mmol) in tetrahydrofuran (75 ml) was added dropwise to a suspension of sodium borohydri- de (2.26 g, 59.7 mmol) in tetrahydrofuran (75 ml). A solution of iodine (5.05 g, 19.9 mmol) in tetrahydrofuran (150 ml) was added dropwise. The solution was warmed to room temperature and heated to reflux for 16 h. It was cooled to 0° C. Methanol (150 ml) was added dropwise. The solvent was removed in vacuo. The solid residue was dissolved in 20% aqueous so- dium hydroxide solution/tert-butyl methyl ether (150 m/i50 ml). The phases were separated.The aqueous phase was extracted with tert-butyl methyl ether (3×150 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using dichloromethane/methanol/10% aqueous ammonia (first: 100:10:1, then 70:30:3) as eluent, to give 1.124 g of 2-(2-(2-(Methylamino)ethyl)phenoxy)ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][OH:9])[N:3]=1.[H-].[Na+].I[CH3:13].O>CN(C)C=O>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][O:9][CH3:13])[N:3]=1
Reactant: OCCn1ccc(Br)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1ccc(Br)n1

Procedure:
To a solution of 2-(3-bromo-1H-pyrazol-1-yl)ethanol obtained in Step D of Example 6 (300 mg) in N,N-dimethylformamide (16 mL) were added sodium hydride (55%, 137 mg) and iodomethane (196 μL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 2 hr, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (150 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:14][O:15][C:16]2[N:24]=[C:23]3[C:19]([N:20]=[C:21]([O:25][CH3:26])[NH:22]3)=[C:18]([NH2:27])[N:17]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C=O)C>[CH:8]1([CH2:14][O:15][C:16]2[N:24]=[C:23]3[C:19]([N:20]=[C:21]([O:25][CH3:26])[N:22]3[CH2:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[C:18]([NH2:27])[N:17]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: BrCC1CCOCC1
Reactant: COc1nc2c(N)nc(OCC3CCCCC3)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCC3CCCCC3)nc2n1CC1CCOCC1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
2-[(Cyclohexylmethyl)oxy]-8-(methoxy)-9H-purin-6-amine trifluoroacetate salt (0.28 g) was heated with anhydrous potassium carbonate (0.3957 g) in anhydrous DMF (5 mL) under nitrogen for 1 hour at 60° C. (external). The reaction mixture was cooled to room temperature before adding 4-(bromomethyl) tetrahydro-2H-pyran (0.14 g) in anhydrous DMF (1 mL). The reaction mixture was heated to 50° C., overnight. The reaction mixture was quenched into water (20 mL) and extracted into ethyl acetate (20 mL, 3 times). The organic layers was separated, combined and then washed with brine (20 mL). The organic layer was separated and then dried by passing through a hydrophobic frit. Evaporation under reduced pressure gave pale yellow oil that solidified on standing. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (30-80%) to give the title compound as a white solid (0.1677 g).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[CH2:13]=[CH:14][CH:15]=[CH:16][CH2:17][CH2:18][CH:19]=[CH2:20].N12CCCC1=NCCC2>C(O)C.C1C=CC=CC=1>[CH2:17]([CH:16]1[C:2]2[C:1](=[O:12])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[C:4](=[O:11])[C:3]=2[CH2:13][CH:14]=[CH:15]1)[CH2:18][CH:19]=[CH2:20]
Reactant: O=C1CCC(=O)C2CC=CC=C12
Reactant: C=CC=CCCC=C
Agent: C1CN=C2CCCN2C1
Solvent: CCO
Solvent: c1ccccc1
Product: C=CCCC1C=CCC2=C1C(=O)C1=C(CCCC1)C2=O
Reaction time: 24 h
Yield: 49.1 %

Procedure:
A mixture of 13.8 g of tetrahydronaphthoquinone (0.085 mole) and 10 g (0.092.5 mole) of 1,3,7-octatriene was refluxed for 11/2 hours in 100 ml of ethanol. After the addition of 1 ml of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), the mixture was stirred while exposed to air for 24 hours. The ethanol was then blown off and the residue was dissolved in benzene and chromatographed on acidic alumina. From the eluate, 11.2 g of crude product were obtained (49% yield). The crude product was rechromatographed on acidic alumina using a 3:1 mixture of cyclohexane/benzene as the eluent. After removal of the solvent, the product was recrystallized from methanol to yield an analytical product having a mp of 47° to 48° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH:17]2[CH:13]([CH:14]=[CH:15][C:16]2=O)[CH:12]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:10])C1C=CC=CC=1.C(OC(OC)=O)(=O)[O:26]C.[H][H]>O1CCCC1.[Pd]>[CH3:1][O:8][C:9]([N:11]1[CH2:18][CH:17]2[CH:13]([C:14](=[O:26])[CH2:15][CH2:16]2)[CH:12]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:10]
Reactant: CCOC(=O)C1C2C=CC(=O)C2CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Reactant: COC(=O)OC(=O)OC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C1C2C(=O)CCC2CN1C(=O)OC
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A mixture of the compound prepared as described in Example 5 (4.70 g), dimethyl pyrocarbonate (3.83 g), and 5% palladium/carbon (1.0 g) in tetrahydrofuran (100 ml) was hydrogenated at a hydrogen pressure of 60 psi and at room temperature. After two hours, the catalyst was removed by filtration and the filtrate concentrated in vacuo to give 3.41 g of compound 9.
Reaction SMILES: C(O)=O.[CH:4]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:16]=3[C:32]([O:34]C(C)(C)C)=[O:33])[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5]1>ClCCl>[CH:4]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[C:16]=3[C:32]([OH:34])=[O:33])[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)c1c(-c2cccc(OCC3CC3)c2)c2ccccc2n1Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: O=CO
Product: O=C(O)c1c(-c2cccc(OCC3CC3)c2)c2ccccc2n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
Formic acid (4 mL) was added dropwise to a stirred solution of tert-Butyl 3-[3-(cyclopropylmethoxy)phenyl]-1-[(4-fluorophenyl)methyl]indole-2-carboxylate (Example 72, 431 mg, 0.91 mmol) in dichloromethane (1.0 mL). The reaction was stirred at room temperature for 8 h, then concentrated in vacuo. The resulting solids were placed on a pad of silica gel and purified by chromatography (gradient from 30% ethyl acetate/hexane to 100% ethyl acetate) to afford 3-[3-(cyclopropylmethoxy)phenyl]-1-[(4-fluorophenyl)methyl]indole-2-carboxylic acid (324 mg, 85%): mp=200-202° C., 1H NMR acetone-d6) 0.32-0.37 (m, 2 H), 0.55-0.61 (m, 2 H), 1.21-1.31 (m, 1 H), 3.86 (d, J=7.0 Hz, 2 H), 5.90 (s, 2 H), 6.89-6.93 (m, 1 H), 7.00-7.08 (m, 4 H), 7.11-7.16 (m, 2 H), 7.18-7.24 (m, 2 H), 7.30-7.36 (m, 2 H), 7.52-7.58 (m, 2 H), 11.28 (br s, 1 H); mass spectroscopy gave MH+=416 (60%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Br:24][CH2:25][C:26]([NH:28][C:29]1[N:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:27].C(OCC)(=O)C.CCCC(C)C>C(#N)C>[Br-:24].[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([NH:28][C:26]([CH2:25][N+:1]23[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]2)[C@@H:3]([O:9][C:10]([C:12]2([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:2]3)=[O:27])[N:30]=1
Reactant: O=C(CBr)Nc1cccnn1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2cccs2)CCCCCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCCC(C)C
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3cccs3)CCCCCC1)C2)Nc1cccnn1
Product: [Br-]
Reaction time: 8 h
Yield: 10.6 %

Procedure:
1-Thiophen-2-yl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 5d) (80 mg) and 2-bromo-N-pyridazin-3-yl-acetamide (Example 5e) (52 mg) were dissolved in acetonitrile (3 mL) and stirred overnight. Ethyl acetate (9 mL) and isohexane (4 mL) were added and stirred overnight. The resulting crystals were filtered off and then triturated with ethyl acetate to afford the titled compound (14 mg).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[C:8]([CH3:14])=[CH:7][C:6]=1[CH3:15].[OH-].[Na+]>CO>[CH:11]1([C:9]2[C:8]([CH3:14])=[CH:7][C:6]([CH3:15])=[C:5]([CH2:4][C:3]([OH:16])=[O:2])[CH:10]=2)[CH2:12][CH2:13]1
Reactant: COC(=O)Cc1cc(C2CC2)c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)c(C2CC2)cc1CC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
2.5 g of (5-cyclopropyl-2,4-dimethyl-phenyl)-acetic acid methyl ester in 30 ml of methanol is kept at ice bath temperature and treated with 0.5 g of sodium hydroxide in 5 portions. The reaction mixture is stirred at room temperature for 1.5 hours. The solvent is removed in vacuo, the residue poured into water and extracted with diethyl ether. The combined organic phases are dried with sodium sulfate, filtered and concentrated to afford 2.3 g of (5-cyclopropyl-2,4-dimethyl-phenyl)-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[N:13]=[C:14]=[O:15].[CH3:16][N:17]([CH2:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]2[CH:32]=[C:31]([NH:33][CH3:34])[N:30]=[CH:29][N:28]=2)[CH:23]=[CH:24][CH:25]=1)[CH3:18].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=[O:15])[N:33]([C:31]1[CH:32]=[C:27]([NH:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][N:17]([CH3:16])[CH3:18])[CH:21]=2)[N:28]=[CH:29][N:30]=1)[CH3:34]
Reactant: CNc1cc(Nc2cccc(CN(C)C)c2)ncn1
Reactant: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3cccc(CN(C)C)c3)ncn2)c1Cl
Temperature: 70 °C
Reaction time: 18 h

Procedure:
2,6-dichloro-3,5-dimethoxyphenylisocyanate (1.25 eq.) is added to a solution of N-(3-dimethylaminomethyl-phenyl)-N′-methyl-pyrimidine-4,6-diamine (93 mg, 0.36 mmol, 1 eq.) in toluene (3 ml), at 70° C. and under an argon atmosphere. The resulting mixture is stirred at 70° C. for 18 h, allowed to cool to RT, and diluted with DCM and a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 9:1) affords 121 mg of the title compound as a white solid: ESI-MS: 504.9/506.9 [MH]+; tR=3.64 min (purity: 100%, gradient J); TLC: Rf=0.12 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=CN=3)=NOC=2C)=NC=1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cn3)noc2C)nc1
Agent: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Product: Cc1onc(-c2ccc(Cl)cn2)c1COc1ccc(C(=O)O)cn1
Yield: 34.3 %

Procedure:
As described for example 283, 6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (250 mg, 0.7 mmol) was converted, instead of 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, to the title compound (83 mg, 35%) which was obtained as a white solid. MS: m/e=344.3 [M−H]−.