Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:6]=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[CH2:29][N:30]2[C@@H:34]([CH3:35])[C@@H:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:32][C:31]2=[O:42])[C:8](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:10]=1.[C:44]1(B(O)O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[CH3:35][C@H:34]1[C@@H:33]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:32][C:31](=[O:42])[N:30]1[CH2:29][C:20]1[CH:21]=[C:22]([C:25]([F:28])([F:26])[F:27])[CH:23]=[CH:24][C:19]=1[C:7]1[C:8]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:43])[CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
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: COCCOC
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1-c1ccccc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
[2′-((4S,5R)-4-Methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-6-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester (0.100 g, 0.16 mmol), phenylboronic acid (0.029 g, 0.24 mmol), potassium carbonate (0.055 g, 0.40 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.018 g, 0.02 mmol) were combined in DME (2 mL) and H2O (1 mL), and the mixture was purged with N2 for 10 minutes. The reaction was stirred at 90° C. for 5 hours, until no starting material was seen by analytical LCMS. The pH was adjusted to pH 7 with saturated aqueous NH4Cl, and the mixture was extracted with EtOAc. The crude material was purified by silica gel chromatography to give the title compound. M+H is 546.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1.S(=O)(=O)(O)O.[OH-].[Na+].[CH2:21](O)[CH3:22]>>[CH2:21]([O:12][C:11]([CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:13])[CH3:22]
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Cc1c[nH]c2ccccc12
Temperature: 0 °C
Yield: 90 %

Procedure:
A mixture of 5.0 g (28.5 mmols) of indole-3acetic acid, 250 ml of ethanol and 5 ml of conc. sulfuric acid was heated under reflux for 2 hours. After cooling to 0° C., the mixture was neutralized with a 2 normal aqueous sodium hydroxide solution. The solvent was evaporated under reduced pressure, and then water was added to the residue followed by extraction of the solution with chloroform. The chloroform layer was washed with an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dried to afford 5.2 g (yield: 90%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: NC1CCCCC1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCCC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (266 mg, 1.0 mmol) was treated with cyclohexylamine following general procedure B to afford 4-cyclohexylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (286 mg). Thus obtained amino-ester (33 mg, 0.1 mmol) was subjected to reaction with ethyl isocyanate according to general procedure C to furnish 3-ethyl-7-methoxy-1-(3-pyrrolidin-1-yl-propyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (15 mg). LCMS: m/z 354 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.58 (s, 1H), 7.58 (m, 1H), 7.50 (m, 1H), 7.41 (m, 1H), 7.24 (m, 1H), 7.06-7.14 (m, 2H), 6.48 (m, 1H), 4.92 (m, 1H), 4.08 (s, 3H), 2.46 (m, 2H), 1.64-1.92 (m, 5H), 1.42 (m, 2H), 1.28 (m, 1H) ppm.
Reaction SMILES: C[O:2][C:3]([C@@:5]12[C:11]([CH3:13])([CH3:12])[C@@H:8]([CH2:9][CH2:10]1)[CH:7]=[C:6]2[C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]([CH3:30])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:23])=[CH:16][C:15]=1[O:31][CH3:32])=[O:4].[Li+].[OH-].O>CO.O>[CH3:32][O:31][C:15]1[CH:16]=[C:17]([C:22]([CH3:30])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:23])[CH:18]=[C:19]([O:20][CH3:21])[C:14]=1[C:6]1[C@:5]2([C:3]([OH:4])=[O:2])[C:11]([CH3:13])([CH3:12])[C@H:8]([CH:7]=1)[CH2:9][CH2:10]2
Reactant: CCCCCCC(C)(C)c1cc(OC)c(C2=C[C@@H]3CC[C@@]2(C(=O)OC)C3(C)C)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCC(C)(C)c1cc(OC)c(C2=C[C@@H]3CC[C@@]2(C(=O)O)C3(C)C)c(OC)c1
Yield: 26 %

Procedure:
Methyl ester 11a (HU-911) 0.103 g (0.233 mmol) and LiOH 0.111 g (4.66 mmol) in 2 ml of MeOH/H2O 3:1 were heated at 200° C. over 48 hrs in a screwed vial under air atmosphere. Water was added to the reaction mixture and extracted several times with ether. Organic phases were collected, dried over MgSO4 and concentrated in vacuo. The product was purified by preparative TLC (hexane/ethyl acetate) to give yellow solid 0.026 g (26%). mp 101-102° C.; 1H NMR (300 MHz, CDCl3) δ ppm 6.46 (s, 2H), 6.32 (d, J=3.40 Hz, 1H), 3.71 (s, 6H), 2.46 (t, J=3.44 Hz, 1H), 2.38-2.44 (m, 1H), 1.80-2.03 (m, 1H), 1.53-1.58 (m, 2H), 1.26 (s, 6H), 1.16-1.24 (m, 7H), 1.14 (s, 3H), 1.03-1.12 (m, 3H), 1.00 (s, 3H), 0.85 (t, J=6.74 Hz, 3H). Exact mass calculated for C28H42O4 m/e 428.29. found 428.98. Anal. calcd. for C28H42O4: C, 75.66; H, 9.41. Found: C, 75.50; H, 9.48.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:29][C:30]([N:38]1[N:42]=[N:41][C:40]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][N:50]([NH2:75])[CH2:51][C@H:52]([OH:74])[C@@H:53]([NH:61][C:62](=[O:73])[C@H:63]([C:69]([CH3:72])([CH3:71])[CH3:70])[NH:64][C:65]([O:67][CH3:68])=[O:66])[CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:45][CH:44]=2)=[N:39]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31]>CN(C=O)C>[CH3:31][C:30]([N:38]1[N:42]=[N:41][C:40]([C:43]2[CH:44]=[CH:45][C:46]([CH2:49][N:50]([NH:75][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:51][C@H:52]([OH:74])[C@@H:53]([NH:61][C:62](=[O:73])[C@H:63]([C:69]([CH3:71])([CH3:70])[CH3:72])[NH:64][C:65]([O:67][CH3:68])=[O:66])[CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)=[CH:47][CH:48]=2)=[N:39]1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH3:29]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Reaction time: 0.25 h

Procedure:
With the exclusion of air, 261 mg (1.38 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 496 mg (2.58 mmol) of EDC and 232 mg (1.72 mmol) of HOBT are dissolved in 7.5 ml of DMF. After 15 min, 0.72 ml (5.17 mmol) of TEA and 585 mg (0.86 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane hydrochloride (Example 25h) in 3.5 ml of DMF are added. After 20 hours, the mixture is worked up as described under Example 25i. Precipitation with DIPE from a concentrated solution in methylene chloride yields the title compound: HPLC20-100 : tRet= 17.5; FAB MS (M+H)+ =814.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([NH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5])[CH3:3].[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[CH3:11][O:10][C:8](=[O:9])[CH2:7][NH:6][C:4](=[O:5])[C@H:2]([CH3:3])[NH2:1]
Reactant: COC(=O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CNC(=O)[C@H](C)N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Boc-Ala-Gly-OMe [10 g, 45 mmoles, described by H. U. Immer et al., Helv. Chim. Acta, 57, 730 (1974)] is dissolved in cold (ice bath) trifluoroacetic acid (100 ml). The solution is stirred for 1 hr at 0° C and the solvent evaporated. The residue is dissolved in methanol, added to diethyl ether and the precipitate collected to yield the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:17]=[CH:16][C:9]2[NH:10][C:11](=[O:15])[CH2:12][S:13](=[O:14])[C:8]=2[CH:7]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:17]=[CH:16][C:9]3[NH:10][C:11](=[O:15])[CH2:12][S:13](=[O:14])[C:8]=3[CH:7]=2)[CH2:31][CH2:30]1
Reactant: O=C1CS(=O)c2cc(OCCCCl)ccc2N1
Reactant: c1ccc2nc(CN3CCNCC3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CS(=O)c2cc(OCCCN3CCN(Cc4ccc5ccccc5n4)CC3)ccc2N1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture consisting of 7-(3-chloropropoxy)-3,4-dihydro-2H-1,4-benzothiazin-3-one-1-oxide (2.02 g, 7.38 mmol), N-(2-quinolylmethyl)piperazine (2.52 g, 11.07 mmol), potassium carbonate (2.04 g, 14.76 mmol), potassium iodide (2.45 g, 14.76 mmol) and DMF (50 ml) was stirred at 80° C. for 4 hours. The solvent was distilled off from the reaction mixture under reduced pressure, followed by the addition of water. The resulting mixture was extracted with chloroform-methanol (10:1). The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column while using chloroform-ammonia-saturated methanol (10:1) as an eluent. Fractions containing the target compound were collected and then concentrated under reduced pressure, whereby 1.23 g of the title compound was obtained as a yellow oil (4.49 mmol, 60.9%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([CH2:19][CH2:20][CH2:21][Cl:22])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: ClCCCBr
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(CCCCl)CC1
Yield: 69.9 %

Procedure:
Piperazine-1-carboxylic acid ethyl ester (3.0 g, 18.9 mmol), K2CO3 (2.8 g, 1.1 eq.), DMF (30 ml, 10 vol) and 1-bromo-3-chloropropane (1.8 ml, 18.9 mmol, 1 eq.) were reacted together at room temperature overnight. The reaction was quenched with water (100 ml) and extracted with DCM (3×50 ml). The combined DCM extracts were dried over MgSO4, filtered washed with DCM and concentrated in vacuo to give the title compound (3.1 g, 70%) as a pale yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[CH2:13]([N:2]([CH3:1])[CH:3]1[CH2:12][CH2:11][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:5][CH2:4]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNC1CCC2(CC1)OCCO2
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CN(Cc1ccccc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
N-Methyl-1,4-dioxaspiro[4.5]decan-8-amine (4.0 g, 23.39 mmol, 1.0 eq.) was dissolved in DCM (70 ml); benzaldehyde (2.83 g, 28.07 mmol, 1.2 eq.) and AcOH (0.2 ml) were added and the mixture was stirred for 30 minutes at RT. NaBH(OAc)3 (14.8 g, 70.17 mmol, 3.0 eq.) was added at 0° C. and the reaction mixture was stirred for a further 14 hours at RT. After monitoring by TLC, water (100 ml) was added to the reaction and the phases were separated. The aqueous phase was extracted with 10% MeOH in DCM (2×100 ml). The combined org. phases were washed in succession with water (100 ml) and sat. NaCl solution (100 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 4% MeOH in DCM). Yield: 49% (3.0 g, 11.49 mmol)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:23]=2[NH:22][CH:21]=[C:20]3[Cl:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.CN(C)C=O>O>[Cl:24][C:20]1[C:19]2[C:23](=[C:15]([NH:14][S:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)=[CH:6][CH:7]=3)(=[O:13])=[O:12])[CH:16]=[CH:17][CH:18]=2)[NH:22][CH:21]=1
Reactant: c1c[nH]cn1
Reactant: O=S(=O)(Nc1cccc2c(Cl)c[nH]c12)c1ccc(CCCBr)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1cccc2c(Cl)c[nH]c12)c1ccc(CCCn2ccnc2)cc1
Temperature: 80 °C
Yield: 77.1 %

Procedure:
To 4-(3-bromopropyl)-N-(3-chloro-1H-indole-7-yl)benzenesulfonamide (213 mg, 0.5 mmol) were added 170 mg (2.5 mmol) of imidazole and 6 ml of dimethylformamide, followed by heating at 80° C. for 3 hours in a nitrogen atmosphere. Then, the reaction mixture was poured into water and extracted with chloroform. The extract was dried over magnesium sulfate and concentrated. Then, the residue was purified by silica gel column chromatography, to give 160 mg of the title compound.
Reaction SMILES: Cl.[C:2]([N:6]([C@@H:10]1[CH2:15][C:14]2[C:16]([O:21]C)=[CH:17][CH:18]=[C:19]([F:20])[C:13]=2[O:12][CH2:11]1)[CH2:7][CH2:8][CH3:9])([CH3:5])([CH3:4])[CH3:3].B(Br)(Br)Br.C(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:2]([N:6]([C@@H:10]1[CH2:15][C:14]2[C:16]([OH:21])=[CH:17][CH:18]=[C:19]([F:20])[C:13]=2[O:12][CH2:11]1)[CH2:7][CH2:8][CH3:9])([CH3:3])([CH3:4])[CH3:5]
Reactant: CCCN([C@H]1COc2c(F)ccc(OC)c2C1)C(C)(C)C
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCCN([C@H]1COc2c(F)ccc(O)c2C1)C(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
(R)-3-(N-tert-Butyl-N-n-propylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran hydrochloride (1.3 g, 3.9 mmol) in dry methylene chloride (40 mL) under nitrogen was cooled on a dry ice-EtOH bath to -50° C. Boron tribromide (0.75 mL, 7.8 mmol) was added dropwise (in 1 min) to the stirred solution above. Five minutes after the addition of boron tribromide was complete, the dry-ice bath was changed to an ice bath (+4° C). After stirring for 4 h at the same temperature the solution was poured on ice (100 g) and solid NaHCO3 was added to adjust pH to 8-9. When the ice had melted the mixture was extracted with ether (4×75 mL). The ether extracts were combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 1.1 g (96% yield) of the title compound as a pale yellow oil. [α]21D =-91.7° (C=10; CHCl3) GC-MS (70 eV) M=281 (6%).
Reaction SMILES: Br[C:2]1[C:3]([N:9]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:11][C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:5]1[N:4]=[C:3]2[C:2]([N:14]([CH3:15])[C:12](=[O:13])[CH2:11][CH2:10][N:9]2[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:7][N:6]=1
Reactant: CNC(=O)CCN(CC(C)C)c1nc(Cl)ncc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)CN1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 100 °C
Yield: 40.7 %

Procedure:
3-[(5-bromo-2-chloro-pyrimidin-4-yl)-(2-methylpropyl)amino]-N-methyl-propanamide (Intermediate 85; 3.26 g, 9.32 mmol)) was suspended in dioxane (70 mL), Caesium Carbonate (6 g, 18.64 mmol) was added and the mixture bubbled with nitrogen for 10 minutes. Tris(dibenzylideneacetone)dipalladium(0) (512 mg, 0.56 mmol) and XANTPHOS (485 mg, 0.839 mmol) were added and the mixture heated at 100° C. for 24 hrs. The reaction mixture was cooled to room temperature, solvent evaporated and the residues partitioned between DCM (250 mL) and water (250 mL). The aqueous phase was re-extracted with DCM (200 mL) and the combined organic phases dried over MgSO4 and evaporated to a dark brown gum which was taken up in DCM and purified on silica, eluting with a gradient of 30-50% Ethyl Acetate/iso-hexane then 50% Ethyl Acetate/iso-hexane. Fractions containing product were combined and evaporated to a yellow solid, which was heated at reflux in iso-hexane (50 mL) for 15 minutes and allowed to cool to room temperature overnight. The resulting solid was filtered and dried to give the title compound as a pale yellow solid (1.02 g, 41%)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.Cl.[C:26]1([S:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:36]3[CH2:37][CH2:38][CH:33]([S:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:34][CH2:35]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: c1ccc(SC2CCNCC2)cc1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCC(Sc4ccccc4)CC3)n2n1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol), 4-(phenylthio)piperidine hydrochloride (128 mg, 0.50 mmol), and N, N-diisopropylethylamine (116 mg, 0.90 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (55-55% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (82.0 mg, 65%). 1H NMR (DMSO-d6) δ: 10.83 (s, 1H), 7.99 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.47 (d, 2H), 7.33-7.42 (m, 3H), 7.26-7.33 (m, 1H), 6.15 (s, 1H), 4.33 (d, J=12.6 Hz, 2H), 3.27 (t, J=10.9 Hz, 2H), 2.37 (s, 3H), 2.03-2.18 (m, 2H), 1.63-1.79 (m, 2H), 1.46 (s, 6H); ESI-MS: m/z 502.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:32])([F:33])[F:19])[CH:22]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3cccc(C(F)(F)F)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(3-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])=[CH:5][C:4]=1[O:16][CH3:17])#[N:2].O1CCCC1.O.[OH-].[Na+]>C(OCC)(=O)C.C(O)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([OH:12])=[O:11])=[CH:5][C:4]=1[O:16][CH3:17])#[N:2]
Reactant: CCOC(=O)C(C)c1ccc(C#N)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(C(C)C(=O)O)ccc1C#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.2 %

Procedure:
To a stirred solution of ethyl 2-(4-cyano-3-methoxyphenyl)propanoate (222 mg, 0.952 mmol) in co-solvent with tetrahydrofuran and water (1:1) were added sodium hydroxide (95 mg, 2.38 mmol). The reaction mixture was stirred for 15 h at room temperature, then acidified to pH 3-4 with acetic acid. The residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(4-Cyano-3-methoxyphenyl)propanoic acid (188 mg) was obtained as 96% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]([CH:31]=O)=[C:25]2[C:30]=1[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]([CH:31]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])=[C:25]2[C:30]=1[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:21])[CH3:18]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: CCOC(=O)c1[nH]c(C=O)c2c1CCCC2
Product: CCOC(=O)c1[nH]c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)c2c1CCCC2

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 3-formyl-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid ethyl ester (48 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18][O:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:12][CH2:11]1.[CH:24]1[C:29]([O:30][C:31](Cl)=[O:32])=[CH:28][CH:27]=[C:26]([Cl:34])[CH:25]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.OS([O-])(=O)=O.[K+].CCOCC>[Cl:34][C:26]1[CH:27]=[CH:28][C:29]([O:30][C:31]([N:9]([CH3:8])[C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]#[C:17][CH2:18][O:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:14][CH2:15]2)=[O:32])=[CH:24][CH:25]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CN[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Reaction time: 0.75 h

Procedure:
A solution of 1.41 g (corresponds to 3.0 mmol) of trans-Methanesulfonic acid 3-(4-methylamino-cyclohexyl)-prop-2-ynyl ester trifluoroacetate in 20 ml CH2Cl2 was first cooled at 0° C., treated with 0.5 ml (3.6 mmol) 4-chlorophenylchloroformate and then with 2.57 ml (15 mmol; 5 equivalents) of Huenig's base (during 3 min). After 45 min at RT, the mixture was dissolved in aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated to give 1.41 g (quantitative) of crude trans-Methanesulfonic acid 3-{4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexyl}-prop-2-ynyl ester, MS: 400 (MH+, 1Cl). The crude product was directly used in the next step.