Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1.[Cu][C:34]#[N:35]>CN1CCCC1=O.O.C(OCC)(=O)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]2[S:21][C:20]([CH3:30])=[N:19][C:18]=2[C:16]([N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]2[CH2:9][C:7]2[NH:6][C:5]3[CH:31]=[CH:32][C:2]([C:34]#[N:35])=[CH:3][C:4]=3[N:8]=2)=[O:17])=[CH:28][CH:27]=1
Reactant: N#C[Cu]
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(Br)ccc3[nH]2)c(-c2ccc(F)cc2)s1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(C#N)ccc3[nH]2)c(-c2ccc(F)cc2)s1
Temperature: 200 °C
Yield: 1 %

Procedure:
A stirring mixture of (RS)-1-[2-(5-bromo-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E34 (25 mg, 0.44 mmol) and copper(I)cyanide (79 mg, 0.88 mmol) in N-methylpyrrolidinone (7 ml) under argon was heated at 200° C. for 5 h. The cooled reaction mixture was diluted with water/ethyl acetate and filtered through Kieselghur. The organic phase was washed with water (2×), brine (2×), dried (MgSO4) and the solvent removed in vacuo. The residue was chromatographed (silica gel, 0-4% methanol (containing 10%.0.880 ammonia)-dichloromethane). Further purification by HPLC (Supercosil ABZ+, 5-95% acetonitrile containing 0.1% trifluoroacetic acid-water containing 0.1% trifluoroacetic acid) afforded the title compound as a pale brown gum (2 mg, 1%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C.[Zn]>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc([N+](=O)[O-])cc3c2CC1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(N)cc3c2CC1
Yield: 97.3 %

Procedure:
A mixture of tert-butyl 9-nitro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.25 g, 0.75 mmol), zinc (1.48 g, 22.6 mmol) and calcium chloride (0.04 g, 0.38 mmol) in 78% ethanol (7.5 mL) was refluxed for 2 h and filtered hot. The filtrate was concentrated in vacuo to dryness to give 0.22 g (99%) of solid as the desired product: MS (EI) m/z 302 (MH+).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:12])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[Cl-].[Cl-].[Cl-].[Al+3].C(S)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:12][C:4]1[C:3]([OH:2])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2
Reactant: COc1ccc2[nH]ccc2c1C
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: Cc1c(O)ccc2[nH]ccc12
Temperature: 5 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
5-Methoxy-4-methyl-1H-indole (400.0 mg, 2.48 mmol) was dissolved in CH2Cl2 in an inert atmosphere, and the mixture was cooled to 5° C. Aluminium trichloride (1.65 g, 12.4 mmol) was added, and the reaction mixture was stirred for 5 min, at which point ethanethiol (770.8 mg, 12.4 mmol) was added dropwise. Stirring was continued for 2 h at 5° C. The mixture was poured into ice water (10 mL), stirred for 20 min, and then NaHCO3 was added until a pH>7 was reached. The mixture was extracted with CH2Cl2 (4×), the combined organic phases dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (EtOAc/hexane (v/v) 1:5) to give 133 mg (36%) of the title compound as a white crystalline solid. 1H NMR (400 MHz, CDCl3): 2.46 (s, 3H), 4.40 (br, 1H), 6.49 (s, 1H), 6.76 (d, 1H), 7.10 (d, 1H), 7.19 (s, 1H), 8.03 (br, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].[I:15]I>>[Cl:1][C:2]1[CH:8]=[C:7]([I:15])[CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1c(Cl)cc(I)cc1Cl
Temperature: 60 °C
Reaction time: 72 h

Procedure:
2,6-Dichloroaniline (16.2 g, 0.1 mol) is suspended in a solution of sodium bicarbonate (8.6 g, 0.1 mol in 100 mL of water) and warmed to 60° C. Elemental iodine (25.4 g, 0.1 mol) is added portionwise and the resulting mixture stirred at 60° C. for 3 days. After cooling to room temperature, the reaction mixture is partitioned between CH2Cl2 (250 mL) and saturated sodium bisulfite solution (500 mL). The aqueous layer is re-extracted with additional CH2Cl2 (250 mL) and the combined organic layers dried (MgSO4) and concentrated by rotary evaporator. The residual oil is purified by flash chromatography (9:1 hexanes/EtOAc) to give 2,6-dichloro-4-iodoaniline (m.p. 100–102° C.).
Reaction SMILES: [CH2:1](OC1C=C(C=CC=1O)C(O)=O)C1C=CC=CC=1.[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1O)[CH2:30][Br:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([CH3:1])[CH:34]=1)[CH2:30][Br:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccc(CBr)cc1OCc1ccccc1
Reactant: O=C(O)c1ccc(O)c(OCc2ccccc2)c1
Product: Cc1cc(CBr)cc(OCc2ccccc2)c1

Procedure:
When 3-benzyloxy-4-hydroxybenzoic acid is used as a starting material and similarly reduced and brominated, 3-benzyloxy-4-hydroxybenzyl bromide used in Example 33 can be obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:20]2[CH2:38][CH2:37][C:23]3([C:27](=[O:28])[N:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=4)[CH2:25][CH2:24]3)[CH2:22][CH2:21]2)[CH2:9]1)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[Br:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:26]2[CH2:25][CH2:24][C:23]3([CH2:22][CH2:21][N:20]([CH2:19][CH:10]4[CH:11]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:12][NH:8][CH2:9]4)[CH2:38][CH2:37]3)[C:27]2=[O:28])=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC(CN2CCC3(CC2)CCN(Cc2ccc(Br)cc2)C3=O)C(c2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N(Cc2ccc(Br)cc2)CCC12CCN(CC1CNCC1c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To 510 mg (0.87 mmol) of 3-(RS)-[2-(4-bromobenzyl)-1-oxo-2,8-diaza-spiro[4.5]dec-8-ylmethyl]-4-(SR)-phenylpyrroli-dine-1-carboxylic acid tert-butyl ester was added a solution of DCM/TFA 20% (12 mL). The reaction mixture was agitated for one hour at room temperature before quenching with 30 mL of aqueous solution of sodium hydroxide (1N). The solution was then extracted with DCM (2×20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated in vacuo yielding Compound 3 as a pale yellow solid (420 mg, 99.4%).
Reaction SMILES: B(Br)(Br)Br.Cl.[F:6][C:7]1[CH:8]=[CH:9][C:10]([O:26]C)=[C:11]2[C:16]=1[O:15][CH2:14][C@H:13]([N:17]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:12]2>C(Cl)Cl>[F:6][C:7]1[CH:8]=[CH:9][C:10]([OH:26])=[C:11]2[C:16]=1[O:15][CH2:14][C@H:13]([N:17]([CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20])[CH2:12]2
Reactant: CCCN(C(CC)CC)[C@H]1COc2c(F)ccc(OC)c2C1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CCCN(C(CC)CC)[C@H]1COc2c(F)ccc(O)c2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
Demethylation was done by addition of BBr3 (2.6 ml, 27.5 mmol) in 10 ml dry CH2Cl2 during 20 min., to a stirred, cooled solution (-70° C.) of (R)-8-fluoro-5-methoxy-3-(N-3-pentyl-N-n-propylamino)chroman hydrochloride (4.44 g, 12.8 mmol) in 100 ml dry CH2Cl2 under N2 atmosphere and dry conditions. The solution was stirred for 1 hour at -70° C., 1 hour at 0° C. and 1 hour at room temp. and was thereafter poured into 80 ml saturated. NaHCO3 aq. under vigirous stirring. After 0.5 hour the layers where separated and the aqueous phase was extracted with 2×15 ml CH2Cl2. The combined organic layers where dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography on silica with a gradient of petroleumether-petroleumether: EtOAc, 4:1 to give 3.72 g of (R)-8-fluoro-5-hydroxy-3-(N-3-pentyl-N-n-propylamino)chroman (NAG 134) as an yellow-brown oil. [α]D22 ×85° (c 1.02 in MeOH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[NH:5][CH:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)[CH3:2].[H-].[Na+].[CH3:23]N(C=O)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[N:5]([CH3:23])[CH:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)NC1CCC=C(C#Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(C)C1CCC=C(C#Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
22 mg (0.082 mmol) (3-phenylethynyl-cyclohex-3-enyl)-carbamic acid ethyl ester are dissolved in 2 ml DMF and 1 mL THF. 8 mg (0.165 mmol) of a 60% dispersion of NaH in oil is added and the mixture stirred under argon for 90 minutes at room temperature. The reaction mixture is cooled to 0°, and 16 microliters Mel in 0.5 ml THF are added dropwise. After stirring one hour at room tenmperature, the reaction mixture is cooled to 0° again, ice is added and the crude product extracted with ethyl acetate, washed with water and saline, dried with sodium sulfate and column chromatographed using a 4:1 mixture of petroleum ether and ethyl acetate. Yield: 43% .
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[C:5]([C:14]([OH:16])=O)[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].C1C=CC2N(O)N=[N:30]C=2C=1.CCN=C=NCCCN(C)C.N>C(Cl)Cl>[C:1]([C:3]1[C:4]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[C:5]([C:14]([NH2:30])=[O:16])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(-c2c(C(=O)O)sc(N3CCOCC3)c2C#N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: ClCCl
Product: Cc1ccc(-c2c(C(N)=O)sc(N3CCOCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
To a solution of 4-cyano-3-(4-methylphenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (0.030 g, 0.091 mmol), HOBT (0.024 g, 0.18 mmol) and EDCI (0.035 g, 0.18 mmol) in DCM (1 mL) was added concentrated aqueous ammonia (0.158 mL, 4.5 mmol). The reaction mixture was allowed to stir at rt for 3 h and was concentrated. The residue was diluted with 0.1N HCl and extracted with EtOAc. The organic solutions were combined, washed with sat NaHCO3, brine, dried over MgSO4, filtered and concentrated to give 4-cyano-3-(4-methylphenyl)-5-morpholin-4-ylthiophene-2-carboxamide (35) (0.024 g, 80%). LCMS: (AA) ES+ 328.2. 1H NMR (400 MHz, d6-DMSO) δ: 7.45-7.47 (m, 2H), 7.40-7.42 (m, 2H), 3.88-3.90 (m, 4H), 3.64-3.66 (m, 4H) and 2.62 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][C:3]([C:11]([OH:13])=O)=[N:2]1.C(Cl)(=O)C(Cl)=O.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([N+:34]([O-:36])=[O:35])[CH:28]=1.[H-].[Na+]>ClCl.CN(C=O)C.C1COCC1>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:11]([C:3]2[CH2:4][C:5]3([CH2:6][CH2:7][O:8][CH2:9][CH2:10]3)[O:1][N:2]=2)=[O:13])=[C:29]([N+:34]([O-:36])=[O:35])[CH:28]=1
Reactant: O=C(O)C1=NOC2(CCOCC2)C1
Reactant: Nc1ccc(-c2ccccc2F)cc1[N+](=O)[O-]
Agent: ClCl
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2ccccc2F)cc1[N+](=O)[O-])C1=NOC2(CCOCC2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
A solution of 1,8-dioxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (87.7 mg, 0.474 mmol, as prepared in the previous step) in CH2 Cl2 (10 mL) was treated with oxalyl chloride (41.3 μL, 0.474 mmol) and DMF (1 drop) at rt for 1 h. Simultaneously, a solution of 2′-fluoro-3-nitro-biphenyl-4-ylamine (100 mg, 0.431 mmol, as prepared in step A of this Example) in dry THF (10 mL) was treated with NaH (51.7 mg, 1.29 mmol, 60% dispersion in oil) at rt for 1 h. The acid chloride solution was concentrated in vacuo, taken up in dry THF (10 mL), and slowly added to the 2′-fluoro-3-nitro-biphenyl-4-ylamine solution. The mixture was allowed to stir for 20 min at rt, quenched with satd aq NH4Cl, diluted with water, and extracted with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 40-g Sepra Si 50 SPE column (Isco system: Flow rate=20 mL/min; Eluent=EtOAc/hexanes, 1:9 v/v for 10 min, then 1:9 to 2:3 v/v over 40 min) to afford the title compound (131 mg, 76%) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 11.58 (s, 1H), 8.87 (d, J=8.8 Hz, 1H), 8.47 (d, J=2.0 Hz, 1H), 7.89 (dt, J=8.8, 1.6 Hz, 1H), 7.47 (td, J=7.7, 1.8 Hz, 1H), 7.35-7.44 (m, 1H), 7.24-7.31 (m, 1H), 7.20 (ddd, J=10.9, 8.3, 1.0 Hz, 1H), 3.92 (ddd, J=11.8, 8.8, 3.2 Hz, 2H), 3.71-3.82 (m, 2H), 3.10 (s, 2H), 1.94-2.03 (m, 2H), 1.83-1.93 (m, 2H). Mass Spectrum (LCMS, APCI pos.): Calcd. for C20H18FN3O5: 400.1 (M+H). found: 400.1.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=1)[CH2:37][C:38]1[S:42][C:41]([NH2:43])=[N:40][N:39]=1>C(#N)C>[Cl:33][C:34]1[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=1)[CH2:37][C:38]1[S:42][C:41]([NH:43][C:19]([C:18]2[CH:22]=[CH:23][C:15]([O:14][C@@H:11]3[CH2:10][CH2:9][C@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)=[N:16][CH:17]=2)=[O:21])=[N:40][N:39]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)O)cn2)CC1
Reactant: Nc1nnc(Cc2cccc(Cl)c2)s1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)Nc3nnc(Cc4cccc(Cl)c4)s3)cn2)CC1
Reaction time: 96 h

Procedure:
0.321 g of cis-6-(4-tert-butoxycarbonylcyclohexyloxy)nicotinic acid (1 mmol, 1 eq.) is placed in 50 mL of acetonitrile at room temperature. 0.33 mL of diisopropylethylamine (2 mmol, 2 eq.), 0.466 g of bromotris-pyrrolidinophosphonium hexafluorophosphonate (1 mmol, 1 eq.) and 0.270 g of 5-(3-chlorobenzyl)[1.3.4]thiadiazol-2-ylamine (1.2 mmol, 1.2 eq.) are successively added with stirring. After 4 days at room temperature, the reaction medium is evaporated and 15 mL of DMF are added. The medium is stirred again for 18 hours, diluted in ethyl acetate, washed three times with brine, dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane ranging from 5% to 50%. After evaporating the fractions of interest, the residue is chromatographed on silica gel with a gradient of ethyl acetate in dichloromethane ranging from 2% to 20%. 0.262 g of tert-butyl cis-4-{5-[5-(3-chlorobenzyl)[1.3.4]thiadiazol-2-ylcarbamoyl]pyridin-2-yloxy}cyclohexanecarboxylate is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:33][CH3:34])=[C:24]([NH:26][S:27]([CH:30]5[CH2:32][CH2:31]5)(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:33][CH3:34])=[C:24]([NH:26][S:27]([CH:30]5[CH2:31][CH2:32]5)(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(=O)(=O)C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)cc1NS(=O)(=O)C1CC1
Yield: 8.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)cyclo propanesulfonamide (80 mg, 0.119 mmol) was hydrolyzed by lithium hydroxide (0.0109 g, 0.238 mmol), THF/Methanol/water (12/8/4 mL) to afford 5 mg (8.19% yield) of the titled compound. 1H NMR (DMSO-d6, 300 MHz): δ 11.8 (s, 1H), 9.04 (s, 1H), 8.44-8.42 (d, 2H), 8.29 (s, 1H), 7.96 (s, 1H), 7.77 (s, 1H), 7.61-7.58 (m, 2H0, 7.20-7.10 (m, 4H), 5.41 (s, 2H), 3.88 (s, 3H), 0.92-0.88 (m, 4H). MS: m/z=517.8 (M+1), HPLC: 84.12% Method B.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][Cl:27])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>C1COCC1>[Cl:27][CH2:26][CH2:25][O:24][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([S:8][C:4]3[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=3)[NH2:1])=[N:13][CH:14]=[N:15]2)=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCl
Reactant: Nc1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(Sc3cccc(N)c3)ncnc2cc1OCCCl
Reaction time: 0.5 h

Procedure:
In a round bottomed flask 3-aminothiophenol (279 mg, 2.23 mmol) was dissolved in 10 mL of dry THF. To this solution was added sodium hydride, 60% suspension in mineral oil, (86 mg, 2.23 mmol) and the reaction stirred for 30 minutes. 4-chloro-7-(2-chloro-ethoxy)-6-methoxy-quinazoline (610 mg, 2.23 mmol) from Example 35A was added as a 10 mL solution in THF, and the reaction stirred overnight at room temperature. The solution was then concentrated to dryness, and partitioned between ethyl acetate and water, and extracted with an additional portion of ethyl acetate. The extracts were combined, dried with magnesium sulfate, filtered, and concentrated to give 3-(7-(2-chloroethoxy)-6-methoxyquinazolin-4-ylthio)aniline as a yellow solid weighing 600 mg. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.47 (d, 2H), 7.17 (m, 1H), 6.83 (s, 1H), 6.72 (m, 2H), 4.51 (m, 2H), 4.05 (m, 3H), 3.89 (s, 3H), 3.51 (bs, 2H); LC-MS (ESI) m/z 362 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C@@:22]([OH:29])([CH2:26][CH2:27][OH:28])[C:23]([OH:25])=O)=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].ClCCl.FC(F)(F)C(O)=O>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:18][C:19](=[O:20])[C@H:21]([C@@:22]2([OH:29])[CH2:26][CH2:27][O:28][C:23]2=[O:25])/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)O)C(=O)OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@]2(O)CCOC2=O)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To No. 5214357, (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoic acid (20 mg, 0.0310 mmol) was added a mixture of dichloromethane/trifluoroacetic acid (9/1, v/v, 2 mL) and the mixture was stirred at room temperature for 1 hour. After confirming the consumption of the starting materials by LCMS, the organic solvent was distilled off under reduced pressure. The resulting residue was purified by preparative HPLC and then freeze-dried to obtain No. 5214805 (11 mg, 56% yield, white powder).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[F:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[CH2:34][C:35]#[N:36]>>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH:22]=[CH:21][C:20]=1[CH2:34][C:35]#[N:36]
Reactant: CC1(C)OB(c2ccc(CC#N)c(F)c2)OC1(C)C
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CC#N)c(F)c1
Yield: 99.8 %

Procedure:
Following Step 1 from General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (350 mg, 1.1 mmol) was reacted with 2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetonitrile (440 mg, 1.7 mmol) to afford the desired product (400 mg, >99%) as a brown solid: ESI MS m/z 365 [C20H13FN2O2S+H]+.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.OC(C(F)(F)F)=O.Br[CH2:18][C:19]([NH2:21])=[O:20].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N:1]1([CH2:18][C:19]([NH2:21])=[O:20])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: NC(=O)CBr
Reactant: C1CNCCNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: NC(=O)CN1CCNCCNCC1
Yield: 141.8 %

Procedure:
Bis-TFA 1,4,7-triazacyclononane (261.4 mg, 0.81 mmol) was dissolved in acetonitrile (5.0 mL), bromoacetamide (168.1 mg, 1.22 mmol) and K2CO3 (225.0 mg, 1.62 mmol) were added sequentially. The mixture was refluxed for 15 hours. Filtration and chromatography of the residue after removal of all volatiles gave the desired product as an oil (214.0 mg, 70%).
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)=[N:25][C:20]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:21][CH:22]=1
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)CCN(CC(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine in an analogous to Example 61e. Product isolated as an off-white solid (0.043 g, 42%). MP: 53-65° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 10.16 (s, 1H), 8.51 (d, 1H, J=8.3 Hz), 8.06 (s, 1H), 8.04 (s, 1H), 7.84 (s, 1H), 7.81 (s, 1H), 7.47 (s, 1H), 7.40-7.31 (m, 2H), 7.18 (t, 1H, J=7.6 Hz), 6.63 (s, 1H), 6.51 (s, 1H), 5.91 (tt, 1H, J=56.1 Hz and 4.0 Hz), 3.85 (s, 3H), 2.98-2.73 (m, 10H). MS: 526.40 (MH)+.
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1.O[Li].O.Cl>C1COCC1.O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([S:5][CH2:4][C:3]([OH:13])=[O:2])=[N:7][CH:8]=1
Reactant: COC(=O)CSc1ccc(Cl)cn1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CSc1ccc(Cl)cn1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To the solution of the ester 14 (0.43 g, 2.0 mmol) in THF (18 mL) was added LiOH.H2O (0.17 g, 4 mmol) as a solution in 5 mL of H2O. The reaction mixture was stirred at room temperature and monitored by TLC. When no staring material was observed, the reaction mixture was acidified with 1N HCl, (˜4.5 mL) and concentrated under reduce pressure to remove the organic solvent. The mixture was diluted with 15 mL of H2O and extracted with EtOAc (2×120 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and dried under high vacuum over P2O5 to give 0.40 g (98% yield) of compound 15 which was used in subsequent reaction without further purification.