Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][NH:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][N:37]2[CH2:44][CH2:43][C:40]3([CH2:42][O:41]3)[CH2:39][CH2:38]2)=[CH:31][CH:30]=1)#[N:28]>O.O1CCCC1>[C:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][N:37]2[CH2:44][CH2:43][C:40]([CH2:42][N:13]([CH3:12])[C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[CH:25][CH:26]=3)([OH:41])[CH2:39][CH2:38]2)=[CH:31][CH:30]=1)#[N:28]
Reactant: CNc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: N#Cc1ccc(CCN2CCC3(CC2)CO3)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(CC1(O)CCN(CCc2ccc(C#N)cc2)CC1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Yield: 49.7 %

Procedure:
A hexane solution of n-butyllithium (1.57M; 2.68 mL) was added dropwise to an anhydrous tetrahydrofuran solution (4.22 mL) of the compound (874 mg) obtained in Step 1 at the internal temperature of below 5° C. and the mixture was stirred under cooling with ice-water for one hour. To the mixture was added dropwise an anhydrous tetrahydrofuran solution (4.22 mL) of the compound (1.02 g) obtained in Step 3 of Example 1 at the internal temperature of below 5° C. over thirty minutes, stirred at the same temperature for one hour and further at room temperature for fifty two hours. To the solution added water (40 mL) under cooling with ice-water and the residue was extracted with ethyl acetate. After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (Chromatorex NH™)(eluent; hexane:ethyl acetate=7:3 to 1:1) to obtain the titled compound (940 mg) as powder.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([NH:16][CH2:17][C:18](O)=[O:19])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>ClCCl>[O:19]=[C:18]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:17][NH:16][C:6](=[O:7])[O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: C1CCNC1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NCC(=O)N1CCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
Pyrrolidine (248 uL, 3 mmol), N-CBZ-glycine (628 mg, 3 mmol), and HOAt (408 mg, 3 mmol) were dissolved in 10 mL of dichloromethane. NMM (0.66 mL, 6 mmol) was added, followed by EDC (575 mg, 3 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with dichloromethane, washed with water, saturated aqueous NaHCO3 solution, and saturated aqueous NH4Cl solution, then dried (Na2SO4) and evaporated to yield phenylmethyl [2-oxo-2-(1-pyrrolidinyl)ethyl]carbamate as a beige solid (782 mg, 100%). LCMS: (M+H)+: 263.1.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[S:8][C:7]1=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].F[C:25]1[N:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28]>CN1C(=O)CCC1.CO>[F:17][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][C:25]3[C:26]([C:27]#[N:28])=[CH:29][CH:30]=[CH:31][N:32]=3)=[CH:14][C:9]=2[S:8][C:7]1=[O:16]
Reactant: N#Cc1cccnc1F
Reactant: O=c1sc2cc(O)ccc2n1CC1CC1(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: N#Cc1cccnc1Oc1ccc2c(c1)sc(=O)n2CC1CC1(F)F
Temperature: 100 °C

Procedure:
To a solution of 3-[(2,2-difluorocyclopropyl)methyl]-6-hydroxy-1,3-benzothiazol-2(3H)-one (18-2) (0.033 g, 0.13 mmol) in anhydrous NMP (1 mL) was added cesium carbonate (0.084 g, 0.26 mmol) and 2-fluoronicotinonitrile (0.024 g, 0.19 mmol). The reaction mixture was then heated under microwave irradiation at 100° C. for 10 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted with methanol and NMP, then filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) gave 2-[(3-{[2,2-difluorocyclopropyl]methyl}-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)oxy]pyridine-3-carbonitrile (18-3) as an off-white solid. HRMS (M+H)+: observed=360.0623, calculated=360.0613.
Reaction SMILES: C([O:8][C:9]1[C:17]([C:18]2[NH:23][C:22](=[O:24])[C:21]([C:25]([O:27][CH3:28])=[O:26])=[C:20]([OH:29])[C:19]=2[CH2:30][CH3:31])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:32])C1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O.[Pd]>[CH2:30]([C:19]1[C:20]([OH:29])=[C:21]([C:25]([O:27][CH3:28])=[O:26])[C:22](=[O:24])[NH:23][C:18]=1[C:17]1[C:9]([OH:8])=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:32])[CH:12]=[CH:11]2)[CH3:31]
Reactant: CCc1c(-c2ccc3c(ccn3C)c2OCc2ccccc2)[nH]c(=O)c(C(=O)OC)c1O
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCc1c(-c2ccc3c(ccn3C)c2O)[nH]c(=O)c(C(=O)OC)c1O

Procedure:
A solution of methyl 6-(4-(benzyloxy)-1-methyl-1H-indol-5-yl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate (Example 373, step 1, 0.086 g, 0.20 mmol) in DCM (5 mL) and EtOAc (2 mL) was hydrogenated under a H2-filled balloon over Pd/C (10% Degussa type, 20 mg) until complete consumption of staring material was observed. The catalyst was filtered off and washed with DCM and EtOAc. The mother liquor was concentrated and the residue was purified by column chromatography (MeOH/DCM, 0-5% gradient). Methyl 5-ethyl-4-hydroxy-6-(4-hydroxy-1-methyl-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate was obtained as a yellowish solid (0.0466 g, 68%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O:22]CC)=[O:21])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.O.[OH-].[Li+:27].Cl>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-:22])=[O:21])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+:27]
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C)CC3)ccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 104.3 %

Procedure:
To ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation D; 43.93 g, 132.2 mmol) in H2O (150 mL) was added lithium hydroxide hydrate (6.31 g, 150.4 mmol). The reaction mixture was heated to 95° C. for 4 hours. The mixture was cooled to ambient temperature and hydrogen chloride (4.626 mL, 4M in dioxane) was added followed by stirring for 10 minutes. Water was removed under reduced pressure, and the residue was dried under vacuum for 16 hours to give the product, lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (42.78 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47]1(/[CH:53]=[CH:54]/[C:55](Cl)=[O:56])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:55](=[O:56])/[CH:54]=[CH:53]/[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:43]=[CH:44][CH:45]=2)=[N:8]1
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccccc1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added (2E)-3-phenylprop-2-enoyl chloride (0.062 g, 0.372 mmol) followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The residue was not purified (yield not calculated). ES-MS (m/z) 733 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[CH:6][C:3]=1[CH:4]=O.[O:12]=[C:13]([CH3:16])[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:11][C:7]1[CH:6]=[C:3]2[C:2](=[C:9]([CH3:10])[CH:8]=1)[O:1][CH2:15][C:14]([C:13](=[O:12])[CH3:16])=[CH:4]2
Reactant: Cc1cc(C)c(O)c(C=O)c1
Reactant: C=CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)C1=Cc2cc(C)cc(C)c2OC1

Procedure:
1.50 g (10 mmol) of 2-hydroxy-3,5-dimethylbenzaldehyde together with 0.66 g (10 mmol) of 3-oxo-1-butene are added at room temperature to a suspension of 0.14 g (1 mmol) of potassium carbonate in 50 ml of 2-butanone. The mixture is brought to reflux with stirring and this temperature is maintained for 90 minutes. The reaction medium is evaporated on a water bath under vacuum, and the residue is taken up with 100 ml of water and extracted 3 times with 75 ml of diethyl ether. The organic phases are combined, washed to neutrality with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated on a water bath under vacuum, and chromatographed on a column of silica (70-230 mesh), eluting with dichloromethane.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C(O[C:20](=O)[C:21](C)([CH3:36])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([Br:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])C)C>C(#N)C>[Br-:35].[C:13]([O:12][C:10]([N:1]1[C:9]2[CH:8]=[CH:7][N+:6]([CH:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]([CH3:36])[CH3:20])=[CH:5][C:4]=2[CH:3]=[CH:2]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)n1ccc2cnccc21
Reactant: CCOC(=O)C(C)(C)CCCCC(C)(Br)c1ccccc1Cl
Solvent: CC#N
Product: CC(C)CCCCC(c1ccccc1Cl)[n+]1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Product: [Br-]
Temperature: 45 °C
Reaction time: 52 h
Yield: 75.5 %

Procedure:
A mixture of tert-butyl 1H-pyrrolo[3,2-c]pyridine-1-carboxylate (0.81 g, 3.73 mmol), 7-bromo-7-(2-chlorophenyl)-2,2-dimethyloctanoic acid ethyl ester (1.40 g, 3.73 mmol) in acetonitrile (25 mL) was stirred and warmed to 45° C. After 52 hours, the reaction was completed. The solvent was evaporated under reduced pressure, the residue was washed with diethyl ether (3×20 mL) to afford 1-tert-butoxycarbonyl-5-[1-(2-chlorophenyl)-6-methylheptyl]-1H-pyrrolo[3,2-c]pyridin-5-ium bromide (1.47 g, 66.5% yield) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CD3OD/TMS) δ (ppm): 10.54 (s, 1H), 8.84 (d, 1H, J=6.9 Hz), 8.23 (d, 1H, J=7.8 Hz), 7.72 (s, 1H), 7.53 (t, 1H, J=4.2 Hz), 7.45 (t, 1H, J=7.2 Hz), 7.39 (d, 1H, J=3.6 Hz), 7.31 (s, 1H), 6.96 (s, 1H), 6.47 (t, 1H, J=7.2 Hz), 4.10 (q, 2H, J=5.7 Hz), 2.72 (d, 2H, J=6.6 Hz), 2.40 (m, 1H), 1.69 (s, 9H), 1.50-1.32 (m, 4H), 1.21 (t, 3H, J=3.3 Hz), 1.12 (s, 6H). (crude mixture. HRMS (DIP-CI): failed, decomposed on analysis.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:22])([F:21])[S:10]([O:13]S(C(F)(F)F)(=O)=O)(=[O:12])=[O:11].O[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28][CH2:27]2.C(=O)([O-])O.[Na+]>ClCCl>[F:8][C:9]([F:22])([F:21])[S:10]([O:13][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28][CH2:27]2)(=[O:12])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.9 %

Procedure:
Firstly 0.22 ml (0.00160 mol) of triethylamine and then 0.26 ml (0.00155 mol) of trifluoromethanesulphonic anhydride were added dropwise under argon to an ice-cold solution of 0.38 g (0.00152 mol) of tert.-butyl 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate in 7.5 ml of dichloromethane. The mixture was stirred at room temperature for 1 hour, poured into saturated sodium hydrogen carbonate solution, extracted with ethyl acetate and completely freed from the solvents. 0.66 g of oily crude tert.-butyl 6-(trifluoromethanesulphonyloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylate was obtained.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C)=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-].C([NH3+])(C)(C)C>O1CCCC1>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:19][CH:20]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(OCc2ccc(CCCCO[Si](C)(C)C(C)(C)C)cc2)c(Cl)c1=O
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(OCc2ccc(CCCCO)cc2)c(Cl)c1=O
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To the product of Example 2E (594 mg, 1.45 mmol) was added anhydrous tetrahydrofuran (3 mL) and a 1.0 M solution of tert-butylammonium fluoride in tetrahydrofuran (2.9 mL, 2.9 mmol). The solution was stirred for 1 hour then concentrated under reduced pressure. Column chromatography [silica gel; eluent pentane-ethyl acetate (1.8:1)] provided the desired product (410 mg, 77%). 1H (CDCl3) δ(ppm): 1.61-1.64 (m, 11H); 1.67-1.74 (m, 2H); 2.68 (t, 2H); 3.68 (t, 2H); 5.23 (s, 2H); 7.23 (d, 2H); 7.33 (d, 2H); 7.74 (s, 1H). 13C (CDCl3) δ(ppm): 27.43, 27.86, 32.56, 35.35, 62.74, 66.36, 71.88, 118.27, 125.18, 127.27, 128.99, 132.28, 143.17, 153.78, 159.07.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:7][CH2:8][CH2:9][C:10]3[CH:16]=[C:15]([C:17]4[N:18]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=5[F:29])[N:19]=[CH:20][N:21]=4)[S:14][C:11]=3[C:12]=2[N:13]=1)#[N:2].OO.C(=O)([O-])[O-:33].[K+].[K+]>O.CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:7][CH2:8][CH2:9][C:10]3[CH:16]=[C:15]([C:17]4[N:18]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=5[F:29])[N:19]=[CH:20][N:21]=4)[S:14][C:11]=3[C:12]=2[N:13]=1)(=[O:33])[NH2:2]
Reactant: N#Cc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Yield: 38 %

Procedure:
Following the procedure to prepare 379, compound 366, hydrogen peroxide, potassium carbonate in water and DMSO were reacted to give 432. Yield 38% MS: (ESI+)=426.1
Reaction SMILES: [K].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[C:21]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:20](Cl)[N:19]=[C:18]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[OH-].[Ca+2:39].[OH-].[CH2:41]([OH:44])[CH2:42][OH:43]>C1(C)C=CC=CC=1>[CH3:3][C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[C:21]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:20]([O:43][CH2:42][CH2:41][OH:44])[N:19]=[C:18]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[Ca:39].[CH3:3][C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[C:21]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:20]([O:43][CH2:42][CH2:41][OH:44])[N:19]=[C:18]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: [Ca+2]
Reactant: OCCO
Agent: [K]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Product: [Ca]
Temperature: 100 °C

Procedure:
10 gms of p-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-[2,2′-bipyrimidin]-4-yl]benzenesulfonamide potassium salt and calcium hydroxide (14.5 gms) were charged to a reaction vessel. Ethylene glycol (30 ml) and toluene (100 ml) were added to the vessel. The reaction mass was heated at a temperature of 100° C. for 5 hours or until the reaction was complete. The resulting suspension was cooled to 25° C., filtered and isolated as the calcium salt of bosentan.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7](B3OC(C)(C)C(C)(C)O3)=[C:6]([O:19][CH3:20])[CH:5]=2)[CH2:3][CH2:2]1.Cl[C:22]1[N:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][N:26]([S:32]([NH:35][C:36]1[S:40][N:39]=[CH:38][N:37]=1)(=[O:34])=[O:33])[CH2:27]2>>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C:22]3[N:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH2:24][CH2:25][N:26]([S:32]([NH:35][C:36]3[S:40][N:39]=[CH:38][N:37]=3)(=[O:34])=[O:33])[CH2:27]4)=[C:6]([O:19][CH3:20])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: O=S(=O)(Nc1ncns1)N1CCc2c(ccnc2Cl)C1
Reactant: COc1cc(C2CC2)ccc1B1OC(C)(C)C(C)(C)O1
Product: COc1cc(C2CC2)ccc1-c1nccc2c1CCN(S(=O)(=O)Nc1ncns1)C2

Procedure:
The title compound was prepared in a manner analogous to Example 1, except that 2-(4-cyclopropyl-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate W) was used in place of (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid and 5-chloro-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2,6-naphthyridine-2(1H)-sulfonamide (Intermediate V) was used in place of 5-bromo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide. [M+H]+=444.0 1H NMR (400 MHz, Acetone-d6) δ ppm: 8.35 (d, J=5.0 Hz, 1H), 8.12-8.17 (m, 1H), 7.10 (d, J=5.1 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 6.82 (d, J=1.6 Hz, 1H), 6.74 (d, J=7.7 Hz, 1H), 4.28-4.43 (m, 2H), 3.76 (s, 3H), 3.43-3.56 (m, 1H), 2.79-3.22 (br. m, 2H), 2.38-2.52 (br. m, 1H), 1.94-2.02 (m, 1H), 0.93-1.03 (m, 2H), 0.71-0.81 (m, 2H)
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][CH2:7]N1CCN(C(OC(C)(C)C)=O)CC1)(=[O:3])N.[ClH:21].[OH2:22]>>[ClH:21].[ClH:21].[CH2:6]([O:5][CH2:4][C:1]([OH:3])=[O:22])[CH3:7]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCN(CCOCC(N)=O)CC1
Agent: Cl
Product: CCOCC(=O)O
Temperature: 60 °C

Procedure:
1 g (0.00348 mol) of tert-butyl 4-(2-carbamoylmethoxyethyl)piperazine-1-carboxylate prepared in Example I.4.3. and 2 ml of water are placed in a 10 ml conical flask. 2 ml of 37% hydrochloric acid solution are added and the mixture is heated on an oil bath at 60° C. for 1 hour. The water is eliminated on a rotary evaporator under reduced pressure. The residue is taken up in toluene. After evaporation, 1.1 g of a pale yellow solid are obtained. This finely ground solid is placed in a Büchi sublimator. The apparatus is placed under vacuum (0.3 mmHg) and heated at 150° C. for 8 hours. 800 mg (88%) of 2-1-piperazinyl)ethoxy acetic acid dihydrochloride are obtained in the form of white crystals. The analyses correspond to those obtained with the compound prepared in Example I.1.4.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[CH:20]=[C:19]([CH:21]=[CH2:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Br[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.[Pd].O>[C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[CH:20]=[C:19](/[CH:21]=[CH:22]/[C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Brc1cccnc1
Reactant: C=Cc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C(=C/c1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2)\c1cccnc1
Temperature: 100 °C
Yield: 22.2 %

Procedure:
A stirred mixture of (R)-indan-1-yl-(6-vinyl-4H-benzo[d][1,3]oxazin-2-yl)-amine (Example 134) (250 mg, 0.86 mmol), 3-bromopyridine (177 mg, 1.12 mmol), tri(o-tolyl)phosphine (21 mg, 0.07 mmol), triethylamine (261 mg, 2.58 mmol) and palladium actetate (7.73 mg, 0.034 mmol) in N,N-dimethylformamide (3 ml) was heated in a sealed tube at 100° C. for 3 h. The reaction mixture was poured into water (20 ml), extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with water (2×20 ml) and brine (20 ml), dried (magnesium sulfate) and evaporated. Further purification by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (dichloromethane/heptane) yielded the title compound as yellow solid (70 mg, 22%). MS (ISP): m/e=368.2 (M+H+); m.p. 132° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]1([C@H:28]([NH2:30])[CH3:29])[CH2:27][CH2:26]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][C@@H:28]([CH:25]4[CH2:27][CH2:26]4)[CH3:29])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: C[C@@H](N)C1CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N[C@H](C)C3CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-cyclopropylethanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 0.17-0.27 (m, 1 H) 0.27-0.36 (m, 1 H) 0.36-0.44 (m, 1 H) 0.44-0.53 (m, 1 H) 0.94-1.07 (m, 1 H) 1.25 (d, J=6.82 Hz, 3 H) 2.43 (s, 3 H) 3.42-3.57 (m, 1 H) 7.66 (dd, J=8.08, 1.52 Hz, 1 H) 7.69-7.75 (m, 1H) 7.78 (d, J=7.58 Hz, 1 H) 8.17 (br. s., 1 H) 8.43 (d, J=6.32 Hz, 2 H) 8.59 (d, J=8.08 Hz, 1H) 8.85-8.95 (m, 1 H) 13.19 (br. s., 1 H). MS m/z [M+H]+ 388.2.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O>[CH2:6]([C:13]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:1][CH:3]2[O:5][CH2:4]2)=[CH:19][CH:20]=1)=[O:14])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: ClCC1CO1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Cc1ccccc1)c1ccc(OCC2CO2)cc1

Procedure:
A 100 ml 3-neck round-bottom flask equipped with a magnetic stir bar, thermometer and reflux condenser was charged with 11.0 g epichlorohydrin, 5.0 g 4-hydroxyphenyl benzyl ketone, and 0.1 ml H2O. The reactants were stirred on a hotplate. NaOH was then added, ~0.2 g per addition, up to a total of 0.95 g NaOH. The rate of NaOH addition was controlled to keep the reaction temperature below 100° C. At the end of the exothermic reaction, excess epichlorohydrin was removed by vacuum distillation with the flask temperature kept below 150° C. The residue was air-dried, then recrystallized twice from ethanol and redried. The yield was 2.8 g (44%), m.p. 81.0°-82.4° C. A 1H-NMR spectrum of this compound, with peak assignments, is provided in FIG. 1.