Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12].B>S(=O)(=O)(O)O.O1CCCC1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[CH2:11][OH:12]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Sc1ccccc1O
Agent: B
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CO)c(Sc2ccccc2O)c1

Procedure:
9-Cyano-6H-dibenz[b,e][1,4]oxathiepin (IIa) may be prepared according to the following general reaction scheme: ##STR6## wherein R2 and R3 are as previously defined, by treating an appropriately substituted (R2 and/or R3) o-aminothiophenol with 2-chloro-4-nitrobenzoic acid in the presence of cuprous oxide to form the corresponding 2-(o-aminophenylthio)-4-nitrobenzoic acid which then is suspended in water, acidified with sulfuric acid, treated with sodium nitrite followed by sodium fluoroborate to obtain the diazonium fluoroborate which is heated in 50% sulfuric acid to obtain the corresponding 2-(o-hydroxyphenylthio)-4-nitrobenzoic acid. The acid product is treated with borane in tetrahydrofuran to form the corresponding 2-(o-hydroxyphenylthio)-4-nitrobenzyl alcohol which is cyclized in the presence of dicyclohexylcarbodiimide (DCC) to form the corresponding 9-nitro-6H-dibenz[b,e][1,4]oxathiepin. The nitro group then is reduced to the 9-amino compound with stannous chloride and the amine is treated with sodium nitrite followed by a mixture of cuprous cyanide and potassium cyanide to obtain the desired 9-cyano-6H-dibenz[b,e][1,4]oxathiepin of formula IIa.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][NH:9][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCCCCCBr
Reactant: NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCNCCc1ccccc1
Yield: 26.2 %

Procedure:
To a mixture of 2-phenylethylamine (1.09 g, 9 mmol) and triethylamine (1.37 g, 13.5 mmol) in toluene (50 mL) was added methyl 7-bromoheptanoate (2.0 g, 9 mmol) and refluxed overnight. The reaction mixture was filtered and concentrated. Flash column chromatography over silica gel using 100% ethyl acetate yielded a yellow oil (0.62 g, 20%) NMR (250 MHz, CDCl3), 1.12-1.40 (4H, m), 1.40-1.72 (4H, m), 2.29 (2H, t), 2.63 (2H, t), 2.75-2.96 (4H, m), 2.96-3.1 (1H, br s), 3.66 (3H, s), 7.00-7.38 (5H, m).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].C1(N=C=NC2CCCCC2)CCCCC1.NC1C=CC=CC=1>C1COCC1.C(#N)C.CN(C)C1C=CN=CC=1>[C:3]([OH:5])(=[O:4])[C:2]([CH2:6][C:7]([OH:9])=[O:8])=[CH2:1]
Reactant: CC(CC(=O)O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: C=C(CC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The enantiomer excess (hereinafter referred to as "e.e.") of the resulting methylsuccinic acid was determined as follows. A part (1.32 mg, 0.1 mmole) of the crude product was dissolved in 2 ml of THF and 2 ml of acetonitrile, and 45.4 mg (0.22 mmole) of N,N'-dicyclohexylcarbodiimide, 2.4 mg (0.02 mmole) of 4-dimethylaminopyridine, and 0.01 ml (0.11 mmole) of aniline were added to the solution, followed by stirring at room temperature overnight. The solvent was removed from the reaction mixture by distillation under reduced pressure. The residue was dissolved in chloroform, washed three times with a 5M hydrochloric acid aqueous solution and then once with a saturated sodium hydrogencarbonate aqueous solution in a successive manner, and dried over magnesium sulfate. The solvent was removed, and the crude dianilide was purified by silica gel column chromatography using diethyl ether as an eluent. The purified dianilide was subjected to high performance liquid chromatography (HPLC) using a chromatograph equipped with CHIRALCEL-OD® (manufactured by Daicel Chemical Industries, Ltd.) (eluent: isopropyl alcohol/hexane=10/90 by volume; detection: UV 254 nm; flow rate: 1 ml/min) to determine the e.e.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:13][C:7]=2[N:6]=1.[CH:22]([OH:25])([CH3:24])C>>[C:22]([NH:9][C:5]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:13][C:7]=2[N:6]=1)=[N:6][CH3:7])(=[O:25])[C:24]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:8]=1
Reactant: CC(C)O
Reactant: CC1CC(=O)NN=C1c1ccc2[nH]c(CCCN)nc2c1
Product: CN=C(NCCCc1nc2cc(C3=NNC(=O)CC3C)ccc2[nH]1)NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 41 %

Procedure:
0.44 g (1.54 mmol) of 6-[2-(3-aminopropyl)-1H-benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 0.43 g (1.71 mmol) of N1 -benzyl-N2 -cyano-0-phenyl-isourea are boiled under reflux in 20 ml of isopropanol for 4 hours. The solid obtained after cooling of the solution to room temperature is suction filtered and recrystallized from methanol. 0.28 g (41%) of colorless crystals melting at 270° C. are obtained.
Reaction SMILES: [Li][C:2]1([CH3:13])[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[Si]([N:21]=[C:22]=S)(C(C)(C)C)(C)C.[Si](Cl)(C(C)(C)C)(C)C>C1COCC1>[C:22]([C:2]1([CH3:13])[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1)#[N:21]
Reactant: CC(C)(C)[Si](C)(C)N=C=S
Reactant: [Li]C1(C)CCCc2cc(C)cnc21
Agent: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCOC1
Product: Cc1cnc2c(c1)CCCC2(C)C#N
Reaction time: 16 h

Procedure:
A solution of 5,6,7,8-tetrahydro-8-lithio-3,8-dimethylquinoline (20 mM) was generated as described in Example 2 and allowed to react with t-butyldimethylsilyl isothiocyanate (20 mM) as described in Example 2. After 0.5 hours a solution of t-butyldimethylsilyl chloride (3.1 g, 20 mM) in THF (10 ml) was added and the mixture allowed to stand for 16 hours at ambient temperature. The reaction was quenched with 2N hydrochloric acid (50 ml). After 1 hour the aqueous layer was separated, basified (to pH9) and extracted with dichloromethane (2×50 ml) and the organic extracts were dried and evaporated. Kugelrohr distillation of the residue gave the nitrile title compound. (2.8 g, 75%) bp. 90°/0.01 mm (bath temp.)
Reaction SMILES: [I:1][C:2]1[C:3](=[O:20])[C:4]2[C:5]([O:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:6]([O:10]C)[N:7]=[CH:8][CH:9]=2>Br.CC(O)=O>[I:1][C:2]1[C:3](=[O:20])[C:4]2[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=2[O:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1nccc2c(=O)c(I)c(-c3ccccc3)oc12
Agent: Br
Solvent: CC(=O)O
Product: O=c1c(I)c(-c2ccccc2)oc2c(=O)[nH]ccc12
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 96.9 %

Procedure:
A suspension of 3-iodo-8-methoxy-2-phenyl-pyrano[2,3-c]pyridin-4-one (0.30 g, 0.791 mmol) in 33% hydrogen bromide solution in AcOH (3 mL) was heated in a microwave oven at 60° C. for 40 minutes. After coiling to RT, the reaction mixture was added to rapidly stirred ice-cold water (30 mL). After stirring for 10 min, the solid was collected by filtration, washed with water and dried in vacuo at 50° C. to give the title compound (0.28 g, 97%) as a white solid. LCMS (Method A): RT=3.74 min, [M+H]+=366.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([C@:8]1([CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:17]2[C:16]3[NH:18][C:19]4[C:24]([C:15]=3[CH2:14][CH2:13][N+:12]=2[CH2:11][CH2:10][CH2:9]1)=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH3:7].C([O-])(=O)C.[K+].C(O)C.[H][H]>C(Cl)Cl.C(O)C.[Pd].O>[CH3:31][O:30][C:28](=[O:29])[C:27]([O:32][CH3:33])=[CH:26][C@@:8]1([CH2:6][CH3:7])[C@@H:17]2[N:12]([CH2:13][CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=4)[NH:18][C:16]=32)[CH2:11][CH2:10][CH2:9]1
Reactant: CC[C@@]1(C=C(OC)C(=O)OC)CCC[N+]2=C1c1[nH]c3ccc(F)cc3c1CC2
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC[C@@]1(C=C(OC)C(=O)OC)CCCN2CCc3c([nH]c4ccc(F)cc34)[C@@H]21

Procedure:
The E and Z isomer mixture of (S)-1-ethyl-9-fluoro-1-(2-methoxy-2-methoxycarbonylvinyl)-2,3,4,6,7,12-hexahydro-1H-indolo[2,3-a]quinolizin-5-ium perchlorate is dissolved at 30° in 10 cc of methylene chloride/ethanol (80:20), and the solution is added to a prehydrogenated mixture of 982 mg of potassium acetate, 2 g of 10% Pd on charcoal and 8 cc of ethanol, as well as 2 cc of water. The mixture is then hydrogenated at room temperature and normal pressure, while stirring, until 8 millimols of hydrogen have been taken up and hydrogen consumption practically stops. After filtering through Hyflo, and washing with 20 cc of methylene chloride/ethanol (80:20), the filtrate is concentrated by evaporation at 30°/20 mm, the residue is dissolved in 20 cc of methylene chloride, mixed at 0° with 20 cc of 2 N ammonia and divided. The organic phase is separated, extracted with 10 cc of methylene chloride, the 1st and 2nd methylene chloride phases are washed with 20 cc of the same water, combined and dried with sodium sulphate. The reaction mixture is concentrated by evaporation at 30°/20 mm, pulverized, and dried in a high vacuum, whereby a mixture of the Z and E isomers of 3-[(1S,12bS)-1-ethyl-9-fluoro-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizin-1-yl]-2-methoxy-propenoic acid methyl ester is obtained in crude form as yellow-brown residue.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:15])[C:4](=[O:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[N:7]=1.Cl.[CH3:17][CH:18]1[CH2:24][O:23][CH2:22][CH2:21][NH:20][CH2:19]1.C(N(CC)CC)C>O1CCCC1>[CH3:15][N:3]1[C:4](=[O:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[N:7]=[C:2]1[N:20]1[CH2:19][CH:18]([CH3:17])[CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CC1CNCCOC1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1COCCN(c2nc(-c3ccncn3)cc(=O)n2C)C1
Reaction time: 15 h
Yield: 60.3 %

Procedure:
To a slurry of 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (113 mg, 0.507 mmol) and 6-methyl-[1,4]oxazepane hydrochloride (100 mg, 0.660 mmol) in tetrahydrofuran (1.1 mL) was added triethylamine (154 mg, 1.52 mmol) at room temperature. The mixture was stirred for 15 hours and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was washed with ether and dried under reduced pressure to afford 1-methyl-2-(6-methyl-[1,4]oxazepan-4-yl)-1H-[4,4′]bipyrimidinyl-6-one (A087) as white solid (92.2 mg, 60%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](Cl)=[N:11][CH:10]=1.[C:34]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])#[N:35].CC(C)([O-])C.[K+].[Cl-].[NH4+]>CS(C)=O>[CH2:40]([O:39][C:37](=[O:38])[CH:36]([C:12]1[CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:9]([C:8](=[O:23])[N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:32])([F:33])[F:1])[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=2)[CH3:24])=[CH:10][N:11]=1)[C:34]#[N:35])[CH3:41]
Reactant: CCOC(=O)CC#N
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C#N)c1cc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 100 °C
Yield: 59 %

Procedure:
A mixture of 1.00 g (2.05 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide, 0.44 ml (4.1 mmol) ethyl cyanoacetate and 0.46 g (4.1 mmol) potassium tert-butoxide in 2 ml dimethyl sulfoxide was stirred at 100° C. over night. After cooling to room temperature 10 ml of a half-concentrated aqueous solution of ammonium chloride was added. The mixture was extracted with 3 portions of ethyl acetate. The combined organic extracts were washed with two portions of water, dried with sodium sulfate and concentrated to give 1.2 g of crude product. Flash chromatography afforded 0.681 g (58.8%) of the title compound as a yellow foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH2:20][NH2:21])[CH:17]=[CH:18][CH:19]=1>CS(C)=O>[Cl:12][C:4]1[N:3]=[C:2]([NH:21][CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Reactant: NCc1cccc(F)c1
Solvent: CS(C)=O
Product: Fc1cccc(CNc2cc(C(F)(F)F)cc(Cl)n2)c1
Temperature: 90 °C
Yield: 44.8 %

Procedure:
To 2,6-dichloro-4-(trifluoromethyl)pyridine (250 mg, 1.157 mmol) was added DMSO (2 ml), TEA (0.194 ml, 1.389 mmol), and (3-fluorophenyl)methanamine (290 mg, 2.315 mmol). The reaction mixture was stirred at 90° C. until completion as indicated by LCMS, about 1 hour. To the crude reaction mixture was added 1.5 ml of DMSO, filtered and purified by prep LC. After lyphilization, 158 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 305.1 (MH+), rt=1.21 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:18]([NH:20][CH:21]1[CH2:23][CH2:22]1)=[O:19])[C:8]2=[O:28].[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[C:29]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:18]([NH:20][CH:21]1[CH2:22][CH2:23]1)=[O:19])[C:8]2=[O:28])(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCCN)cc2c1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCOc1ccc2ncn(-c3cc(C(=O)NC4CC4)ccc3C)c(=O)c2c1

Procedure:
3-[6-(2-Aminoethoxy)-4-oxoquinazolin-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide (0.1 g), acetyl chloride (0.025 ml), and triethylamine (0.074 ml) were stirred in methylene chloride (2 ml) under an atmosphere of argon for 2 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water (2×), brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 10% methanol/ethyl acetate gave the title compound (0.067 g) as a white solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 1.82 (s, 3H), 2.14 (s, 3H), 2.86 (m, 1H), 3.47 (m, 2H), 4.13 (m, 2H), 7.52 (m, 2H), 7.59 (s, 1H), 7.74 (d, 1H), 7.83 (s, 1H), 7.90 (d, 1H), 8.09 (t, 1H), 8.20 (s, 1H), 8.43 (d, 1); Mass Spectrum: M+H+ 421.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:12])[NH:6]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([N:6]1[C:7]2[C:3](=[C:2]([F:1])[C:10]([F:11])=[CH:9][CH:8]=2)[CH2:4][C:5]1=[O:12])(=[O:15])[CH3:14]
Reactant: O=C1Cc2c(ccc(F)c2F)N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)Cc2c1ccc(F)c2F
Temperature: 0 °C

Procedure:
2.00 g (11.8 mmol) 4,5-difluoro-1,3-dihydro-indol-2-one I were stirred in 6.62 mL (55.0 mmol) acetic anhydride for 2 h at 150° C. The reaction mixture was added to ice water, the precipitated solid was suction filtered and washed with water. The product was recrystallised from a mixture of water and ethanol, suction filtered and dried.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH:7]1[C:15]2[C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12]([N+:20]([O-])=O)=[CH:11][C:10]=2[N:9]([C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH3:35])=[C:29]([O:36][CH3:37])[C:28]=3[O:38][CH3:39])=[O:24])[CH2:8]1)(=[O:4])=[O:3]>C1COCC1.O=[Pt]=O>[NH2:20][C:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[C:15]2[CH:7]([CH2:6][O:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH2:8][N:9]([C:23]([C:25]3[NH:26][C:27]4[C:32]([CH:33]=3)=[CH:31][C:30]([O:34][CH3:35])=[C:29]([O:36][CH3:37])[C:28]=4[O:38][CH3:39])=[O:24])[C:10]=2[CH:11]=1
Reactant: COc1cc2cc(C(=O)N3CC(COS(C)(=O)=O)c4c3cc([N+](=O)[O-])c3ccccc43)[nH]c2c(OC)c1OC
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: COc1cc2cc(C(=O)N3CC(COS(C)(=O)=O)c4c3cc(N)c3ccccc43)[nH]c2c(OC)c1OC
Yield: 76.1 %

Procedure:
A solution of 14o (162 mg, 0.29 mmol) in THF (15 mL) was hydrogenated over PtO2 at 55 psi for 2 h. After removal of the catalyst, the solution was concentrated to a small volume under reduced pressure below 25° C. and diluted with iPr2O to give a crude product. This was purified by precipitation from an EtOAc solution with petroleum ether at 20° C. to give 5-amino-1-[(methanesulfonyloxy)methyl]-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-benz[e]indole (15o) (116 mg, 76%) as an unstable solid, mp >260° C. 1H NMR [(CD3)2SO] δ 11.41 (d, J=1.6 Hz, 1 H, NH), 8.08 (d, J=8.5 Hz, 1 H, H-6), 7.76 (d, J=8.3 Hz, 1 H, H-9), 7.67 (s, 1 H, H-4), 7.49 (t, J=7.6 Hz, 1 H, H-8), 7.30 (t, J=7.6 Hz, 1 H, H-7), 7.04 (d, J=2.0 Hz, 1 H, H-3'), 6.96 (s, 1 H, H-4'), 6.15 (v br s, 2 H, NH2), 4.66 (dd, J=10.9, 8.5 Hz, 1 H, H-2), 4.47 (dd, J=9.9, 3.4 Hz, 1 H, H-2), 4.41 (d, J=10.9 Hz, 1 , CHHO), 4.17 (t, J=9.2 Hz, 1 H, CHHO), 4.13-4.04 (m, 1 H, H-1), 3.94 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 3.07 (s, 3 H, SO2CH3). Anal. Calculated for C26H27N3O7S: C, 59.4; H, 5.2; N, 8.0. Found: C, 59.3; H, 5.4; N, 8.1%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C@@H:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:24][C:25]1[C:30]([F:31])=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1.[F-].[Cs+]>CO.O>[F:24][C:25]1[C:30]([F:31])=[C:29]([C:2]2[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([O:9][C@@H:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[N:19]3[N:23]=[CH:22][CH:21]=[N:20]3)[CH3:11])[CH:3]=2)[CH:28]=[CH:27][N:26]=1
Reactant: C[C@@H](Oc1cc(Br)cnc1N)c1cc(F)ccc1-n1nccn1
Reactant: OB(O)c1ccnc(F)c1F
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CO
Product: C[C@@H](Oc1cc(-c2ccnc(F)c2F)cnc1N)c1cc(F)ccc1-n1nccn1
Temperature: 80 °C
Yield: 79.8 %

Procedure:
5-Bromo-3-[(R)-1-(5-fluoro-2-[1,2,3]triazol-2-yl-phenyl)-ethoxy]-pyridin-2-ylamine (example 45) (200 mg, 0.529 mmol, 1.0 eq) and 2,3-difluoropyridin-4-ylboronic acid (168 mg, 1.06 mmol, 2.0 eq) were dissolved in MeOH (5 mL), followed by the addition of freshly prepared aqueous solution of CsF (563 mg, 3.5 mmol, 7 eq) in water (3.34 mL) and Pd-132 (64 mg, 0.09 mmol, 0.17 eq), then degassed for three times. The mixture was heated up to 80° C. for overnight. LCMS showed >80% conversion to desired product, and ˜10% of des-bromation of example 45. The reaction mixture was filtered. The filtrate was concentrated and purified via a Biotage silica gel cartridge to provide the title compound (174 mg) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:25]1[CH:24]=[C:23]([C:22]2[CH2:21][C:20](=[O:36])[NH:19][C:9]3[CH:10]=[C:11]([N:14]4[CH:18]=[CH:17][CH:16]=[CH:15]4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccccn3)c2)=Nc2ccc(-n3cccc3)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-4-pyrrol-1-yl-phenyl}-carbamic acid tert-butyl ester (Example M50) (290 mg, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (73 mg).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(C(Cl)=O)=O.[NH2:25][C:26]1[C:27]([CH3:34])=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[CH3:32].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[CH:7][C:3]=1[C:4]([NH:25][C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]([OH:33])[C:27]=1[CH3:34])=[O:6]
Reactant: Cc1cc(-c2cccc(F)c2)cc(C(=O)O)c1F
Reactant: Cc1ccc(O)c(C)c1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(F)c2)cc(C(=O)Nc2c(C)ccc(O)c2C)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.7 %

Procedure:
To a solution of 2-fluoro-5-(3-fluorophenyl)-3-methyl-benzoic acid (intermediate III(f)) (597 mg, 2.41 mmol, 1.1 eq) in CH2Cl2 (15 mL) and DMF (5 drops) was added (COCl)2 (916 mg, 7.22 mmol, 3.3 eq) at 0° C. The reaction mixture was stirred at room temperature for 1.5 h. The resulting mixture was concentrated under reduced pressure to remove the solvent and excess reagent and the residue obtained dissolved in THF (20 mL) and added dropwise to a solution of 3-amino-2,4-dimethylphenol (intermediate X(c)) (300 mg, 2.18 mmol, 1.0 eq) and NaHCO3 (920 mg, 10.9 mmol, 5 eq) in THF (20 mL) at 0° C. After the addition was completed, the reaction mixture was stirred at room temperature for 1 h. Water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered, and evaporated in vacuo. The residue was purified by column chromatography (CH2Cl2:MeOH, 500:1 to 300:1) to give the title compound as a white solid (270 mg, 34%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=3)[C:4]=2[CH:3]=1.[CH2:18]([C:20]1[N:25]=[C:24]([Sn](C)(C)C)[CH:23]=[N:22][CH:21]=1)[CH3:19]>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([C:20]1[N:25]=[C:24]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][N:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=4)[C:4]=3[CH:3]=2)[CH:23]=[N:22][CH:21]=1)[CH3:19]
Reactant: CCc1cncc([Sn](C)(C)C)n1
Reactant: Fc1cccc(-n2ncc3cnc(Cl)cc32)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CCc1cncc(-c2cc3c(cn2)cnn3-c2cccc(F)n2)n1
Temperature: 150 °C
Yield: 41.3 %

Procedure:
To a solution of 6-chloro-1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridine (85 mg; 0.34 mmol) and tetrakis(triphenylphosphine)palladium (40 mg, 0.034 mmol) in N,N-dimethylacetamide; 2.0 mL was added (6-ethylpyrazin-2-yl)-trimethyl-stannane (185 mg, 0.684 mmol). The reaction was purged with N2 for 5 min then heated at 150° C. for 45 min in biotage microwave. The reaction mixture was filtered through celite and concentrated. The crude product was diluted with EtOAc then washed with water. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 50% EtOAc) to give 6-(6-ethylpyrazin-2-yl)-1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridine (45 mg) in 41% yield. MS (ESI) m/z: 321.2