Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=2[O:6][CH:5]=1.[C-:15]#[N:16].[Na+]>>[CH3:14][O:13][C:12]1[C:7]2[O:6][CH:5]=[C:4]([CH2:3][CH2:2][C:15]#[N:16])[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc2c(CCBr)coc12
Reactant: [C-]#N
Agent: [Na+]
Product: COc1cccc2c(CCC#N)coc12
Yield: 97.2 %

Procedure:
This compound was prepared by the same method as for intermediate 27, using 2.87 g (11.25 mmol) of 3-(2-bromoethyl)-7-methoxybenzofuran and 1.1 g (22.5 mmol) of sodium cyanide, to afford 2.2 g (97%) of the title compound: MS (ESI) m/z 201 [M]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CS(C)=O.CCOC(C)=O>[CH2:10]([NH:9][C:7]([CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: NC(=O)C1CCNCC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)C1CCNCC1
Yield: 34.7 %

Procedure:
4-Piperidinecarboxamide (10.2 g, 78.0 mmol) in DMSO (10 mL) was treated with benzyl bromide (20.0 mL, 168 mmol). The mixture was diluted with EtOAc and washed with 1N aq. HCl, 5N aq. NaOH, dried over MgSO4, and concentrated to give 5.90 g (35%) of N-benzyl-4-piperidinecarboxamide. [1H]-NMR(CDCl3) consistent with structure.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[C:13]([S:15](O)(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=3[Cl:19])[N:7]=[CH:6][C:5]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:26]>O=P(Cl)(Cl)Cl>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[C:13]([S:15]([Cl:26])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=3[Cl:19])[N:7]=[CH:6][C:5]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:3][CH2:2]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnn(-c2cc(S(=O)(=O)O)ccc2Cl)c1C1CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnn(-c2cc(S(=O)(=O)Cl)ccc2Cl)c1C1CC1
Temperature: 95 °C
Yield: 95.1 %

Procedure:
A mixture of ethyl 5-cyclopropyl-1-(2-chloro-5-{hydroxysulfonyl}phenyl)-1H-pyrazole-4-carboxylate (1.48 g, 4.0 mmol) and PCl5 (1.79 g, 8.6 mmol) in POCl3 (6 mL) under a nitrogen atmosphere was heated at 95° C. for 30 min, cooled to 23° C. and poured slowly over ice. The resulting mixture was extracted with EtOAc. The organic layer was washed three times with cold water, brine, dried over MgSO4, filtered and concentrated in vacuo to afford 1.48 g (95% yield) of ethyl 5-cyclopropyl-1-(2-chloro-5-{chlorosulfonyl}phenyl)-1H-pyrazole-4-carboxylate as a yellow oil.
Reaction SMILES: C(OC(NCCCl)=O)(C)(C)C.[NH2:12][NH2:13].F[C:15]1[C:28]2[C:27](=O)[C:26]3[CH:25]=[N:24][CH:23]=[CH:22][C:21]=3[C:20](=[O:30])[C:19]=2[C:18]([O:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])=[CH:17][CH:16]=1.ClC1C2C(=O)C3C=NC=CC=3C(=O)C=2C(OS(C2C=CC(C)=CC=2)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C>C1COCC1>[C:38]1([CH3:41])[CH:39]=[CH:40][C:35]([S:32]([O:31][C:18]2[CH:17]=[CH:16][C:15]3[NH:13][N:12]=[C:27]4[C:26]5[CH:25]=[N:24][CH:23]=[CH:22][C:21]=5[C:20](=[O:30])[C:19]=2[C:28]=34)(=[O:33])=[O:34])=[CH:36][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(F)c3c2C(=O)c2ccncc2C3=O)cc1
Reactant: NN
Agent: CC(C)(C)OC(=O)NCCCl
Agent: Cc1ccc(S(=O)(=O)Oc2ccc(Cl)c3c2C(=O)c2ccncc2C3=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2ccc3[nH]nc4c3c2C(=O)c2ccncc2-4)cc1

Procedure:
(2-N-tert-butoxycarbonylaminoethyl)hydrazine is prepared by reaction of N-t-butoxycarbonyl-2-chloro-ethylamine with hydrazine following a procedure adapted from J. Med. Chem. 7, 493, (1964). Under a nitrogen atmosphere a solution of (2-N-tert-butoxycarbonylaminoethyl)hydrazine (9.2 g) in anhydrous THF (10 mL) is added during 30' to the stirred 9:1 mixture of 9-fluoro-6-(p-toluenesulfonyloxy)benzo[g]isoquinoline-5,10-dione and 9-chloro-6-(p-toluenesulfonyloxy)benzo [g]isoquinoline-5,10-dione of Preparative Example 15b (3.0 g) in THF (25 mL) containing N,N-diisopropylethylamine (1.38 mL). A slightly exothermic reaction ensues, and the reaction temperature increases from 21° C. to 24° C. After stirring for one hour at room temperature the obtained precipitate is recovered by suction, washed with THF/n-hexane 1/1 (15 mL) and dried at 40° C. under vacuum, to give 2-[2-(N-tert-butoxycarbonylamino)ethyl[-5-(p-toluenesulfonyloxy)iso-quino[8,7,6-cd]indazole-6(2H)-one (1.33 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:16])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.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>[CH3:15][C:14]1[N:13]=[C:12]([NH2:16])[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:21]2[CH:20]=[N:19][C:18]([CH3:17])=[CH:23][CH:22]=2)[CH:7]=1
Reactant: Cc1nc(N)ccc1Oc1ccnc(Cl)c1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cc(Oc3ccc(N)nc3C)ccn2)cn1
Temperature: 85 °C
Yield: 88.7 %

Procedure:
A mixture of Example A7 (2.8 g, 11.88 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.38 g, 15.45 mmol) and K2CO3 (3.28 g, 23.76 mmol) in dioxane 48 mL) and water (12 mL) was sparged with Ar, treated with Pd(PPh3)4 (1.373 g, 1.188 mmol) and heated at 85° C. overnight. The mixture was cooled to RT, diluted with EtOAc, the solids removed via filtration through diatomaceous earth and the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was treated with MeCN, the solid collected via filtration and re-purified via silica gel chromatography (MeOH/DCM) to afford 6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-amine (3.08 g, 89%). 1H NMR (400 MHz, DMSO-d6): δ 9.56 (d, J=2.4 Hz, 1 H), 8.96 (d, J=5.7 Hz, 1 H), 8.71 (dd, J=8.1, 2.4 Hz, 1 H), 7.86 (d, J=2.4 Hz, 1 H), 7.76 (d, J=8.1 Hz, 1 H), 7.66 (d, J=8.7 Hz, 1 H), 7.18 (dd, J=5.7, 2.4 Hz, 1 H), 6.94 (dd, J=8.6, 0.7 Hz, 1 H), 5.86 (s, 2 H), 2.97 (s, 3 H), 2.59 (s, 3 H); MS (ESI) m/z: 293.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([CH3:15])=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH3:16][NH:17][CH3:18]>C(O)C>[CH3:16][N:17]([CH3:18])[C:4](=[O:5])[C:3]1[CH:8]=[C:9]([CH3:15])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=1[OH:1]
Reactant: COC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Reactant: CNC
Solvent: CCO
Product: Cc1cc(C(=O)N(C)C)c(O)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
Methyl 2-hydroxy-5-methyl-3-nitrobenzoate (5.0 g) was dissolved in a solution of dimethylamine in ethanol (33% w/v; 50 ml) and the solution was heated at 100° C. in a sealed pressure vessel for 20 hours. The solvent was removed in vacuo and the residue was triturated with hydrochloric acid (2 N; 50 ml), and washed with water. Recrystallisation from methanol gave N,N-dimethyl-2-hydroxy-5-methyl-3-nitrobenzamide (3.0 g), m.p. 160°-162° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:12])[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2)[CH3:2].[CH2:13]([Li])[CH2:14]CC.CN(C)CCN(C)C.ICC.[NH4+].[Cl-]>C1COCC1>[CH2:1]([C:3]1([CH2:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2]
Reactant: CCC1=c2ccccc2=NC1=O
Reactant: [Li]CCCC
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1(CC)C(=O)Nc2ccccc21
Temperature: 25 °C
Yield: 47.6 %

Procedure:
A solution of 3-ethyl-indol-2-one (16 g, 0.1 mol) in dry THF (200 ml) under N2 was cooled to −25° C. and treated drop wise with n-butyllithium (2.5M in hexanes, 80 ml, 0.2 mol). To the resulting solution was added N,N,N′,N′-tetramethylethylenediamine (30 ml, 0.2 mol). After 30 min. iodoethane (8 ml, 0.1 mol) was added and the reaction mixture was allowed to warm to RT and stirred over night. The reaction mixture was poured into an aqueous NH4Cl solution, extracted with EtOAc (2×) and the combined organic layers were washed with dil. HCl, water, brine, dried (MgSO4) and concentrated. The residual oil was triturated with hexane to afford 3,3-diethylindol-2-one (9 g, 45%), m p. 156-159° C.; 1H NMR (DMSO-d6) δ 10.44 (s, 1H), 7.70-7.69 (t,1H), 7.62-7.59 (m, 1H), 7.58 (d, 1H J=1.7 Hz), 7.53-7.50 (m, 1H), 7.45-7.41 (t, 1H), 7.36-7.35 (m, 1H), 7.34-7.33 (m, 1H), 6.91-6.89 (d, 1H J=8.2 Hz), 1.87-1.80 (m, 2H), 1.77-1.70 (m, 2H), 0.54-0.50 (t, 6H); MS (+ESI) m/z 190 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.Br[C:37]#[C:38][Si:39]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41]>C1(C)C=CC=CC=1.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:37]#[C:38][Si:39]([CH:40]([CH3:42])[CH3:41])([CH:46]([CH3:48])[CH3:47])[CH:43]([CH3:45])[CH3:44])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)[Si](C#CBr)(C(C)C)C(C)C
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)[Si](C#Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.9 %

Procedure:
To a stirred solution of 8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (10 g, 0.0454 mol) and copper sulfate (1.13 g, 0.00454 mol) in toluene (100 mL) was added potassium carbonate (12.5 g, 0.0909 mol) and 1,10 phenanthroline (1.6 g, 0.00909 mol). The reaction mixture was stirred for 5 min at RT. Bromoethynyl triisopropylsilane (13.0 g, 0.0499 mol) was added to the reaction mixture at the same temperature. After completion of addition, the reaction mixture was stirred overnight at 80° C. After completion of reaction (monitored by TLC), the mixture was cooled to RT, diluted with water (500 mL), and extracted with EtOAc (3×500 mL). The organic layer was dried over anhydrous sodium sulfate and solvent was removed under pressure. The product was purified by column chromatography (1% MeOH:DCM in silica 100-200 mesh, diameter of column—5 cm, height of silica—approx. 5 inch) to provide the desired compound as a dark brown colored oil (8.0 g, 44% yield).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[NH3:16]>CC(O)C>[CH:12]1([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:16])[C:3]3=[C:10]([I:11])[N:9]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: N
Reactant: Clc1nccn2c(C3CCC3)nc(I)c12
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCC3)nc(I)c12
Temperature: 115 °C

Procedure:
A Parr bomb containing 8-chloro-3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazine (759 mg, 2.3 mmol) in IPA (100 mL) was saturated with NH3(g) for 5 min at 0° C. then sealed and heated at 115° C. for 38 h. The reaction mixture was then concentrated under reduced pressure, partitioned between DCM (200 mL) and H2O (50 mL) and extracted with DCM (50 mL). Combined organic fractions were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a white solid; 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J=4.8 Hz, 1H), 7.01 (d, J=5.2 Hz, 1H), 5.63 (br, 2H), 3.73 (quintetd, J=0.8 Hz, 8.4 Hz, 1H), 2.60-2.38 (m, 4H), 2.20-1.90 (m, 2H); MS (ES+): m/z 315.9 (100) [MH+]; HPLC: tR=1.75 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:18][C@@H:19]2[O:45][C@H:44]([CH2:46][O:47][C:48](=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50])[C@@H:36]([O:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[C@H:28]([O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C@H:20]2[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[N:10][N:11](C=O)[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].O>CO>[CH2:1]([C:8]1[C:9]([O:18][C@@H:19]2[O:45][C@H:44]([CH2:46][O:47][C:48](=[O:53])[C:49]([CH3:50])([CH3:52])[CH3:51])[C@@H:36]([O:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[C@H:28]([O:29][C:30](=[O:35])[C:31]([CH3:32])([CH3:34])[CH3:33])[C@H:20]2[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:24])[CH3:25])=[N:10][NH:11][C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(Cc2ccccc2)c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)nn1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c1Cc1ccccc1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
To a solution of 4-benzyl-1-formyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (1.49 g) in methanol (15 mL) was added sodium bicarbonate (0.337 g) under stirring at room temperature. The reaction mixture was stirred at room temperature for 11 hours. After confirming the completion of the reaction, water was added to the mixture to precipitate the crystals. The crystals were collected by filtration, and the obtained crystals were washed with water and dried under reduced pressure to give 4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole (1.40 g).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH2:27][CH2:28]O)[CH:24]=[CH:25][CH:26]=1>>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: OCCc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Product: O=C(O)CNC(=O)c1ccc(OCCc2cccc(C(F)(F)F)c2)cc1
Yield: 50.1 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (502 mg, 2.00 mmol) prepared in Example 1 (1a) and 2-[3-(trifluoromethyl)phenyl]ethanol (330 μL, 2.20 mmol) to give 368 mg of the title compound (white powder, yield: 80%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH:21]=3)[C:16]([S:31]([CH3:33])=[O:32])=[CH:15]2)=[N:12][CH:13]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[CH:37][C:36]=1B(O)O>C(O)(CC)(C)C.O>[CH2:42]([O:41][C:38]1[CH:37]=[CH:36][C:35]([F:34])=[C:40]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])[CH:21]=4)[C:16]([S:31]([CH3:33])=[O:32])=[CH:15]3)=[N:12][CH:13]=2)[CH:39]=1)[CH3:43]
Reactant: CS(=O)c1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: CCOc1ccc(F)c(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)(C)O
Product: CCOc1ccc(F)c(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N5CCOCC5)cc43)nc2)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (0.185 g, 1.34 mmol) and (Ataphos)2PdCl2 (0.032 g, 0.044 mmol) were added under an argon atmosphere to a solution of (1-(5-bromopyrimidin-2-yl)-3-(methylsulfinyl)-1H-indol-6-yl)(morpholino)methanone (0.2 g, 0.445 mmol) and 2-fluoro-5-ethoxyphenylboronic acid (0.165 g, 0.89 mmol) in tert-amylalcohol (8.0 mL) and water (0.8 mL). The reaction mixture was stirred at 90° C. for 4 h, then cooled to ambient temperatures and filtered over celite. The filtrate was concentrated and the residue purified by flash column chromatography [silica; dichloromethane with 2% methanol]. White solid. Yield: 0.14 g (62% of theory)
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(CC)CC.CCOC(C)=O>CN(C=O)C.O>[Cl:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH2:12]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)c(Cl)c1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)C3CCCCC3)C2)c(Cl)c1
Yield: 93.8 %

Procedure:
A solution of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride (610 mg), cyclohexanecarbonyl chloride (267 mg) and Et3N (0.76 ml) in DMF (15 ml) was stirred at ambient temperature for 8 hours. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with brine and dried over MgSO4 The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylcarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (630 mg).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:23])[NH:10]2)=[O:4].C1(C)C=CC=CC=1.B.CSC>C1COCC1>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:5]([C@@H:3]([OH:4])[CH2:2][Br:1])=[C:6]2[C:11]=1[NH:10][C:9](=[O:23])[CH:8]=[CH:7]2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: Cc1ccccc1
Product: O=c1ccc2c([C@@H](O)CBr)ccc(OCc3ccccc3)c2[nH]1
Temperature: 1 °C
Reaction time: 0.29 h

Procedure:
A dry 5 liter flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser was charged with 5-Bromoacetyl-8-benzyloxycarbostyril (100 gms/0.268 moles) and dry THF (1.2 liter) under argon. A solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-(1H,3H)-pyrrolo[1,2-c][1,3,2]-oxazaborolidine catalyst in toluene (43 ml/0.388 moles) was added and reaction mass was chilled to 0-2° C. Then, 1M solution of borane-methyl sulfide (32.42 ml/0.3417 moles) in THF (342 ml) was added in 3 hours while maintaining temperature at 0-2° C. The reaction was stirred for another 15-20 minutes at same temperature. The reaction mass was quenched by addition of methanol (171 ml) in 15-20 minutes. The temperature of resulting solution was raised to 25-30° C. and concentrated to a volume of 500 ml under vacuum at 50° C. To this concentrate was added a mixture of water (1.45 liters) and concentrated HCl (74 ml) in 10-15 minutes. The resulting suspension was stirred for 30 minutes at 25° C. The solid 8-benzyloxy-5-[(R)-(2-bromo-1-hydroxyethyl)]-carbostyril obtained was isolated by filtration and washed with water till neutral pH, dried under vacuum at 60-65° C. for 12-14 hours. Yield-70-73 gms.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18]([O:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:18]([O:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][O:15][CH2:14][C@@H:9]1[CH2:10][C@H:11]([F:13])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrC/C=C\COCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1COC/C=C\COCc1ccccc1
Temperature: 0 °C
Yield: 77.6 %

Procedure:
To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinylmethanol (2.46 g, 11.2 mmol) in THF (100 ml), sodium hydride (60% in oil; 896 mg, 22.4 mmol) was added in portions under stirring at 0° C. in a nitrogen gas stream. After stirring at the same temperature for 20 minutes, a solution of (Z)-4-benzyloxy-1-bromo-2-butene (2.76 g, 11.2 mmol) in THF (100 ml) was added. The reaction mixture was stirred for 5 minutes. To the reaction mixture was added tetra-n-butyl ammonium iodide (100 mg, 0.27 mmol) at 0° C. and the mixture was stirred for 15 minutes. The reaction mixture was stirred further at room temperature for 19 hours. Water (50 ml) was added while stirring the reaction mixture under ice cooling, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 120 g), whereby from hexane/ethyl acetate (4/1) eluate fractions, the title compound (3.30 g, 78%) was obtained as a colorless oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH2:3]([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCOc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC#CCOc1ccc(C(=O)O)cc1
Reaction time: 18 h
Yield: 100 %

Procedure:
26 ml (262 mmol) of an aqueous solution of sodium hydroxide having a concentration of 10N are added to a solution of 13.4 g (65.7 mmol) of methyl 4-but-2-ynyloxybenzoate diluted in 200 ml of tetrahydrofuran and 25 ml of water. The reaction medium is stirred at reflux for 5 h then at 45° C. for 18 h. The reaction medium is hydrolysed, diluted with ethyl acetate then brought to pH=6 using an aqueous solution of hydrochloric acid having a concentration of 1N. The product is extracted with ethyl acetate. The organic phase is washed with water then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated. 12.5 g (100%) of 4-but-2-ynyloxybenzoic acid are obtained in the form of a white solid.
Reaction SMILES: C([O:5][C:6](=[O:45])[CH2:7][N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH:37]=[CH:36][CH:35]=[N:34]3)=[CH:29][CH:28]=2)[NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)(=[O:19])=[O:18])[N:10]=1)(C)(C)C.C(OC(=O)CN(C(OC(C)(C)C)=O)C1C=CC=C(C(CC2C=CC(C3C=CC=CN=3)=CC=2)NS(C2C=NC=CC=2)(=O)=O)N=1)(C)(C)C.[OH-].[Na+]>>[N:33]1([C:30]2[CH:29]=[CH:28][C:27]([CH2:26][CH:15]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:18])=[O:19])[C:11]3[N:10]=[C:9]([NH:8][CH2:7][C:6]([OH:45])=[O:5])[CH:14]=[CH:13][CH:12]=3)=[CH:32][CH:31]=2)[CH:37]=[CH:36][CH:35]=[N:34]1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-n3cccn3)cc2)NS(=O)(=O)c2ccccn2)n1
Agent: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-c3ccccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNc1cccc(C(Cc2ccc(-n3cccn3)cc2)NS(=O)(=O)c2ccccn2)n1
Yield: 185.4 %

Procedure:
Reaction was carried out in the same manner as in Example 19-(b) except for using tert-butyl[tert-butoxycarbonyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-yl)amino]acetate (440 mg, 0.611 mmol) obtained in Example 21-(a) in place of tert-butyl[tert-butoxycarbonyl(6-{[4-(pyridin-2-yl)benzyl]-(pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-yl)amino]acetate. After completion of the reaction, the reaction solution was adjusted to pH 4.5 with a 2N aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. To the resulting residue were added ethyl acetate (4 ml) and diisopropyl ether (16 ml), followed by sonication at 40° C. for 15 minutes. The solvent was distilled off under reduced pressure, and then dried under reduced pressure to afford the title compound (542 mg) as a white foam. (Yield: 97%)