Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([C:14]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[NH:11]2)=[C:7]([CH3:23])[CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(#N)C.O>[CH:17]1([NH:16][C:14]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[C:7]([CH3:23])[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:13]=3)=[O:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: Cc1cc(OCCBr)cc2[nH]c(C(=O)NC3CCCCC3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(OCCN2CCOCC2)cc2[nH]c(C(=O)NC3CCCCC3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a stirred solution of 6-(2-bromoethoxy)-N-cyclohexyl-4-methyl-1H-indole-2-carboxamide (I-9A-c: 0.1 g, 0.26 mmol) in acetonitrile (5 mL) at 0° C. was added Cs2CO3 (172.7 mg, 0.53 mmol) followed by morpholine (46.12 mg, 0.53 mmol) dropwise. The resulting reaction mixture was stirred at room temperature for 16 h, diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined ethyl acetate layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to afford 70 mg (70%) of N-cyclohexyl-4-methyl-6-(2-morpholinoethoxy)-1H-indole-2-carboxamide (9A) as a white solid.
Reaction SMILES: [C:1]([N:8]1[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][O:10][CH:9]1[C@H:17]([NH2:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].O>CO.O>[C:1]([N:8]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][O:10][CH:9]1[C@H:17]([NH2:26])[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COC(=O)C1=COC([C@H](N)CCc2ccccc2)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(C(=O)O)=COC1[C@H](N)CCc1ccccc1

Procedure:
A solution of methyl N-Boc-2-[(1R)-1-amino-3-phenylpropyl]-4-oxazolecarboxylate (388 mg) and potassium carbonate (1.5 g) in 90% methanol/water (10 mL) is brought to gentle reflux for 40 min. The reaction mixture is cooled, water is added and extracted thrice with ethyl acetate. The aqueous layer is acidified to pH 3 and extracted three times with ethyl acetate. The combined organic layer is washed twice with brine, dried (Na2SO4) and concentrated. The crude title product (372 mg) was >95% pure by NMR: 1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9H), 2.18 (m, 1H), 2.22 (m, 1H), 2.69 (m, 2H), 5.01 (m, 1H), 5.88 (bs, 1H, NH), 7.16 (m, 3H), 7.23 (m, 2H), and 8.01 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][N:3]=1.C[O-].[Na+].[OH:12][CH2:13]C1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.C(OC)=O.CNC>[NH4+].[Cl-].[Cu].CN(C=O)C>[CH3:13][O:12][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Reactant: Nc1cc(Br)ccn1
Agent: [Cu]
Agent: CNC
Agent: C[O-]
Solvent: COC=O
Solvent: CN(C)C=O
Product: COc1ccc(N)nc1
Yield: 17 %

Procedure:
Method a: 2-Amino-4-bromopyridine (0.10 g; 0.58 mmol), sodium methoxide (0.16 g; 2.9 mmol) and copper powder nanosized activated (0.11 g; 1.74 mmol) were introduced in a screw cap vial (Pyrex glass) together with 2.0 mL of anhydrous MeOH and a stirrer bar. The vial was closed and put in an oil bath at 135° C. and stirred for 14 h. The mixture was cooled, diluted with MeOH (5.0 mL) and filtered through an SPE silica gel cartridge and the product eluted with AcOEt. The fractions were collected and evaporated obtaining a crude of 92 mg of product which was further purified by FCC (DCM/AcOEt=1:1) to give 26 mg (yield 36%) of the title compound as brown oil. Method b: 2-Amino-4-bromopyridine (0.10 g; 0.58 mmol), sodium methoxide (0.16 g; 2.9 mmol) and copper powder nanosized activated (0.11 g; 1.74 mmol) were introduced in a microwave glass tube with 1.5 mL of anhydrous DMF and sealed. The tube was introduced in the microwave cavity and heated for 30 min at 140° C. (140 C30 M75 W300 Psi). Although DMF is a high boiling solvent, high pressure was observed, probably caused by the partial methanolysis of the DMF resulting in low boiling products such as methyl formate and dimethylamine. The mixture was diluted with 10 mL of 2 M NH4Cl solution and extracted 3 times with AcOEt. The organic phase was washed 2 times with 2 M NH4Cl solution and 1 time with water to remove the remaining DMF, dried on NaSO4, and filtered. After the solvent was removed, the crude product was purified by FCC (AcOEt) to afford 12 mg (yield 17%) of the title compound as brown oil. 1H NMR (270 MHz; CDCl3), δ 7.74 (1H, d, 3JHH=3.0 Hz), 7.06 (1H, dd, 3JHH=9.0 Hz, 4JHH=3.0 Hz), 6.45 (1H, d, 3JHH=9.0 Hz), 3.95 (2H, bs, NH2), 3.74 (3H, s, OCH3); m/z (EI-MS): 124 (M+), 109 ([M−CH3]+).
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]([N:19]=[C:20](OC)[CH2:21][CH2:22][CH2:23]Cl)#[N:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:17]([N:19]=[C:20]1[CH2:21][CH2:22][CH2:23][N:1]1[C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]1[OH:16])#[N:18]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: COC(CCCCl)=NC#N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCC2=NC#N)[C@@H]1O
Temperature: 25 °C
Yield: 12.2 %

Procedure:
A solution of trans-4-amino-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (5.0 g), methyl N-cyano-4-chlorobutyrimidate (7.36 g), triethylamine (4.8 ml), and toluene (12 ml) was stirred at 100° C. for 2 days. After being cooled to room temperature, the reaction mixture was concentrated. The residue was taken up in ethyl acetate and washed with brine, dried over anhydrous magnesium sulfate, and concentrated. After purification by column chromatography on silica gel (elution with chloroform-methanol 25:1), the crude product was further purified by recrystallization from ethyl acetate to give trans-4-(2-cyanoiminopyrrolidin-1-yl)-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (0.87 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>>[CH3:36][O:35][C:33]([C:32]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=3)[C:10]([F:12])([F:11])[F:13])=[C:4]([Cl:24])[CH:3]=2)=[CH:28][C:27]=1[O:26][CH3:25])=[O:34]
Reactant: COC(=O)c1ccc(B(O)O)cc1OC
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1OC

Procedure:
In analogy to Example 150, step 2, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 165, step 3) was reacted with 3-methoxy-4-methoxycarbonylphenylboronic acid to give the title compound as an off-white solid. MS (m/e)=510.2 [M+H+].
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([CH:13]1[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH:14]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])#N.C(O)(=[O:32])C>C1C=CC=CC=1.C(OCC)C>[CH:11]([CH:13]1[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH:14]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[O:32]
Reactant: N#CC1CCC2(OCCO2)C1CCCCCCCO
Reactant: CC(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=CC1CCC2(OCCO2)C1CCCCCCCO
Temperature: 25 °C

Procedure:
A solution of diisobutylaluminium hydride (53 g.) in dry benzene (145 ml.) was added, with rapid stirring, to a solution of 7-cyano-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (43.2 g.) in dry diethyl ether (432 ml.) at 10°-15° C. Stirring at ambient temperature was continued for 11/2 hours and the mixture was added to 2 N aqueous acetic acid (1 liter) at a temperature lower than 15° C. The organic phase was separated and the aqueous layer was extracted with diethyl ether. The combined organic phases were washed with aqueous sodium bicarbonate, dried over sodium sulphate, the solvents removed in vacuo and the residue distilled under reduced pressure to give 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (25.3 g.), b.p. 164°-200° C./0.04-0.05 mm.Hg, νmax. 1710 cm-1, 2700 cm-1 (liquid film).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1.[NH2:32][C@H:33]([CH2:37][OH:38])[C@@H:34]([CH3:36])[OH:35].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[OH:38][CH2:37][C@@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][Si:13]([CH:14]([CH3:15])[CH3:16])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19])[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29])[C@H:34]([OH:35])[CH3:36]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: C[C@@H](O)[C@H](N)CO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@H](CO)[C@@H](C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.7 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (2.05 g, 4.58 mmol) synthesized in Example (106c) was dissolved in methanol (20 mL), and commercially available L-threoninol (1.50 g, 14.27 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (2.85 g, 10.30 mmol) were added, followed by stirring at room temperature for 3 days under nitrogen atmosphere. After the solvent was distilled off under reduced pressure, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=3%-7%) to afford the desired compound (2.10 g, yield 86%) as a white foam.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]1([N:11]2[CH:15]=[C:14]([CH:16]=O)[CH:13]=[N:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[NH2:19][CH2:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:25][CH2:24]1)=[O:22]>CO.[Cl-].[Zn+2].[Cl-]>[F:36][C:34]1[CH:33]=[CH:32][C:31]([C:37]([F:39])([F:38])[F:40])=[C:30]([CH:35]=1)[C:29]([N:26]1[CH2:27][CH2:28][N:23]([C:21](=[O:22])[CH2:20][NH:19][CH2:16][C:14]2[CH:13]=[N:12][N:11]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:15]=2)[CH2:24][CH2:25]1)=[O:41]
Reactant: O=Cc1cnn(-c2ccccc2)c1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Product: O=C(CNCc1cnn(-c2ccccc2)c1)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Reaction time: 8 h
Yield: 18.7 %

Procedure:
A mixture of sodium cyano borohydride (100 mg, 1.6 mmol) and zinc chloride (100 mg, 0.73 mmol) was added in portions to a cold solution of 1-phenyl-1H-pyrazole-4-carbaldehyde (60 mg, 0.35 mmol) and 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (142 mg, 0.38 mmol) in methanol (10 ml) and stirring was continued at room temperature overnight. The reaction mixture was concentrated under reduced pressure to get the residue. The residue was quenched with saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by preparative HPLC [(Column-AU/SP/C18-28/006, mobile phase-0.1% TFA in water (A)/acetonitrile (B), flow: 6 mL/minute, gradient: (% B)-0:20; 2:30; 8:70)]) to afford 32 mg (18.8% yield) of 1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-[(1-phenyl-1H-pyrazol-4-ylmethyl)-amino]-ethanone. LCMS Purity: 98.11%. 1H NMR (DMSO-d6): δ 9.2 (s, 2H), 8.6 (d, 1H), 8.0-7.76 (m, 4H), 7.62 (m, 2H), 7.4 (t, 1H), 4.2-4.0 (d, 4H), 3.8 (s, 1H), 3.66-3.44 (m, 4H), 3.3 (d, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][CH3:24])[CH:19]=2)[CH:14]([C:25]2[CH:30]=[CH:29][C:28]3[O:31][CH2:32][O:33][C:27]=3[CH:26]=2)[CH2:13]1.Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C)C=O>[C:36]([CH2:35][O:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][CH3:24])[CH:19]=2)[CH:14]([C:25]2[CH:30]=[CH:29][C:28]3[O:31][CH2:32][O:33][C:27]=3[CH:26]=2)[CH2:13]1)([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(=O)CBr
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1O)CC2c1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)OCC)CC2c1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a slurry of sodium hydride (5 mg, 0.21 mmol) in dimethylformamide (0.5 ml) was added (1RS,3RS)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (0.058 g, 0.14 mmol) at ice-bath temperature under argon. After stirring for 15 min, ethyl bromoacetate (50 μl, 0.2 mmol) was added and the solution stirred for 1 h at room temperature. The product was partitioned between ethyl acetate and 3M aq HCl. The organic extract was washed with water, sat. aq. NaHCO3 solution and finally brine. After drying (MgSO4 anhydrous) filtration and evaporation followed by chromatography gave (1RS,3RS)-3-(2-carboethoxymethoxy-4methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (0.041 g). The product was dissolved in hot ethanol (10 ml) and 1 M aq. NaOH added (1 ml) The mixture was refluxed for 1 h then cooled, acidified with 6M-aqueous HCl and extracted with ethyl acetate. After evaporation the residue was crystallized from ethyl acetate/hexane to give the title compound (0.035 g, 93%). m.p. 177-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:52][S:53]([NH2:56])(=[O:55])=[O:54].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:25])([CH3:26])[C:27]([NH:56][S:53]([CH3:52])(=[O:55])=[O:54])=[O:29])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NS(C)(=O)=O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
A solution of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (16 g, 0.028 mol) prepared in Example 1f and CDI (9 g, 0.056 mol) in DMF (70 mL) was heated at 65° C. for 2 h. Then to this solution was added a mixture of methanesulfonamide (16 g, 0.168 mol) and NaH (5.6 g, 60%, 0.14 mol) in DMF (100 mL), which had been mixed and stirred at room temperature for 2 h. After the resulting mixture was stirred at room temperature for 2 h, it was poured into water and the aqueous solution was acidified to “pH” 1-2 by addition of concentrated HCl. After the aqueous phase was extracted with EtOAc twice, the combined organic layers were dried over anhydrous Na2SO4, concentrated and the residue was purified by recrystallized to give the title compound (11.4 g).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.CN(C=O)C.[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1>CCOCC.CC(C)=O>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:4]2[CH:5]=[C:6]([C:7]#[N:8])[C:2]([NH2:1])=[N:3]2)=[CH:19][CH:18]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)c1ccc(Cn2cc(C#N)c(N)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 23.5 %

Procedure:
To a solution of 3-amino-1H-pyrazole-4-carbonitrile (1.211 g, 11.21 mmol) in anhydrous DMF (20 ml) K2CO3 (5.414 g, 39.24 mmol) was added. The suspension was stirred 5 min at room temperature and treated with p-bromomethylbenzoic acid methyl ester (2.568 g, 11.21 mmol), stirred for 2.5 hrs at 100° C., cooled and filtered. Filtrate was evaporated to form an oily residue, which was dissolved in a mixture Et2O-acetone and kept overnight at −10° C. A crystalline material was formed which was triturated with hot EtOAc, again kept overnight at −10° C. and was collected by filtration to form the title compound 95 (675 mg, 24% yield). LRMS: 256.3 (calc.), 257.3 (found).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[C:4]([Cl:11])[N:3]=1.CC(CC)=O.[CH2:17]([NH2:19])[CH3:18].[OH-].[Na+]>O>[CH2:17]([NH:19][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[C:4]([Cl:11])[N:3]=1)[CH3:18]
Reactant: CSc1c(Cl)nc(Cl)nc1Cl
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCC(C)=O
Product: CCNc1nc(Cl)c(SC)c(Cl)n1
Temperature: 5 °C

Procedure:
45.9 Grams of 2,4,6-trichloro-5-methylthio-pyrimidine, 150 g of methylethylketone and 130 g of water are introduced into a 250 ml reactor provided with a stirrer. To this mixture maintained at 5° C. are added in a period of 30 minutes 9.44 g of ethylamine in 32.5% aqueous solution. The temperature of 5° C. is maintained for one and one half hours. Then 8.08 g of caustic soda in 30% aqueous solution are added. The mixture is maintained at 20° C. for 4 hours and over night in a refrigerator at about 0° C. A precipitate appears which is isolated by filtration, washed with 16 ml of methylethylketone and recrystallized twice from 180 ml of ethanol. 10.5 G of 2-ethylamino-4,6-dichloro-5-methylthio-pyrimidine are thus obtained, which melts at 147° C. and which is identified by its infra-red spectrum (IR) and it nuclear magnetic resonance spectrum (NMR).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17](O)=[O:18])[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH:33]([CH3:35])[CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:21][C:2]([CH3:1])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([N:36]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:32][CH:33]([CH3:35])[CH3:34])=[O:18])[N:6]=1)=[O:4]
Reactant: CC(C)CNCC(C)C
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)N(CC(C)C)CC(C)C)c2c1
Temperature: 25 °C

Procedure:
To a solution of 28.3 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid in 1 mL DMF was added 23.0 mg HOBt, 19.4 mg diisobutylamine, 38.3 mg EDC, and 45.2 mg DIEA in that order. The mixture was stirred at room temperature over night and purified by RP-HPLC using 65-100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound as white solid. LC-MS: 4.29 min. (m/Z=402.3, 424.3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Li+].[OH-].C(O)(=O)C>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOc1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: O=C(O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOc1cccnc1
Reaction time: 18 h

Procedure:
To a solution of 1.3 g (2.7 mmol) of ethyl 8-(p-chlorophenylsulfonamido)-4-[2-(3-pyridyloxy)ethyl]-octanoate in 8.1 ml acetonitrile is added 2.7 ml (5.4 mmol) 2M LiOH solution in water. After 18 h at room temperature, the reaction mixture is diluted with 9.5 ml water and filtered to remove a small amount of insoluble solid. The filtrate is acidified with 0.36 g (5.94 mmol) acetic acid and stirred in an ice bath. After 2 h the solid is filtered, washed with water and dried. Recrystallization from acetonitrile gives pure compound of example 31, namely 8-(p-chlorophenylsulfonamido)-4-[2-(3-pyridyloxy)ethyl)-octanoic acid, m.p. 86°-88°; further recrystallization gives m.p. 89°-91°. Compound forms potassium salt as hydrate (containing 1.5 moles water).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2Cl.[CH3:13][N:14]([CH2:16][CH2:17][CH2:18][NH2:19])[CH3:15]>N1C=CC=CC=1.C(Cl)Cl.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[NH:19][CH2:18][CH2:17][CH2:16][N:14]([CH3:15])[CH3:13]
Reactant: Clc1nccc2c(Br)cccc12
Reactant: CN(C)CCCN
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CN(C)CCCNc1nccc2c(Br)cccc12
Reaction time: 0.13 h
Yield: 25 %

Procedure:
To a microwave vial containing 5-bromo-1-chloroisoquinoline (Step 3, 0.300 g, 1.2 mmol), dissolved in pyridine (3 mL), was added Dimethylaminopropyl-amine (0.16 mL, 1.3 mmol). The mixture was placed into CEM Microwave for 8 minutes at 100° C., while supplying 80 Watts of power via power-max. The mixture was diluted with DCM and water, and extracted with DCM (3×10 mL). Then dried organics (over sodium sulfate) was filtered, and concentrated in-vacuo. It was then purified by Amino-Propyl Silica-gel chromatography in MeOH/DCM. This gave tan colored oil, which was titled product (0.085 g, 0.3 mmol). MS (ESI pos. ion) m/z: 309; 310 (M+H). Calc'd Exact Mass for C14H18N3Br: 308