Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[N:43][C:42]=2[C:52]2[C:53]([F:59])=[C:54]([CH:56]=[CH:57][CH:58]=2)[NH2:55])[CH:38]=[CH:37][N:36]=1.[O:60]1[CH:64]=[CH:63][CH:62]=[C:61]1[S:65](Cl)(=[O:67])=[O:66]>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[N:43][C:42]=2[C:52]2[C:53]([F:59])=[C:54]([NH:55][S:65]([C:61]3[O:60][CH:64]=[CH:63][CH:62]=3)(=[O:67])=[O:66])[CH:56]=[CH:57][CH:58]=2)[CH:38]=[CH:37][N:36]=1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: O=S(=O)(Cl)c1ccco1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccco1
Yield: 63 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (3.0 g, 7.6 mmol) and furan-2-sulfonyl chloride (1.4 g, 8.4 mmol) the title compound of Step A was obtained (2.5 g, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (d, J=5.5 Hz, 1H), 7.59-7.66 (m, 1H), 7.42-7.75 (br, 1H), 7.13-7.20 (m, 2H), 7.02 (d, J=5.5 Hz, 1H), 6.93-6.98 (m, 1H), 6.37-6.42 (m, 2H), 3.50-3.57 (m, 4H), 3.72-3.78 (m, 4H). MS (ES+): 522 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][C:17]=1[C:29]([NH:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:30].C(OCC)(=O)C>CN(C)C=O.O>[C:8]1([CH2:7][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][C:17]=2[C:29]([NH:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:30])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCc1ccc(O)c(C(=O)Nc2cccnc2)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Reaction time: 1 h

Procedure:
Cesium carbonate (171 mg, 0.53 mmol) and benzyl bromide (0.05 ml, 0.42 mmol) were added to a solution of ethyl 3-{4-hydroxy-3-[(3-pyridinylamino)carbonyl]phenyl}propanoate (may be prepared as described in Description 98; 110 mg, 0.35 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred for one hour and then ethyl acetate (10 ml) and water (10 ml) were added. The organic layer was separated, washed further with water (3×10 ml), dried (MgSO4) and the solvent removed in vacuo to yield the title compound as a yellow solid. 126 mg.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:2]([C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.CO.[OH-].[Na+]>O1CCCC1>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:2]([C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a stirred solution of 2.5 g of methyl 6-[([1,1'-Biphenyl]-2-carbonyl)amino]-pyridine-3-carboxylate in 50 ml of 1:1 tetrahydrofuran:methanol is added 10 ml of 5N sodium hydroxide and the mixture stirred at room temperature for 16 hours. The reaction mixture is concentrated in vacuo to a residue which is dissolved in water and neutralized with acetic acid. The separated colorless solid is filtered and air dried to give 2.0 g of the desired product:M+ =318.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[CH3:66][N:67]1[CH2:72][CH2:71][N:70]([NH2:73])[CH2:69][CH2:68]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:73][N:70]5[CH2:71][CH2:72][N:67]([CH3:66])[CH2:68][CH2:69]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCN(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)NN2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 62.4 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.014 g (0.12 mmole) 4-methyl-piperazin-1-ylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.034 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-methyl-piperazin-1-yl) benzamide (I-118) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[C:5]2[NH:6][C:7](=[O:10])[CH:8]=[CH:9][N:4]2[N:3]=1.N1C[CH2:20][CH2:21][N:22]2[CH2:28]CCCC[C:23]=12.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CN(C)CCO.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[C:5]2[N:6]=[C:7]([O:10][CH2:20][CH2:21][N:22]([CH3:28])[CH3:23])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: C=CCOC(=O)c1c(N)nn2ccc(=O)[nH]c12
Reactant: C1CCC2=NCCCN2CC1
Agent: CN(C)CCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C=CCOC(=O)c1c(N)nn2ccc(OCCN(C)C)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 35 %

Procedure:
To a mixture of allyl 2-amino-5-oxo-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylate (1 g, 4.270 mmol) in MeCN (15 mL) was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (975.1 mg, 957.9 μL, 6.405 mmol) and benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphonium (Phosphorus Hexafluoride Ion) (2.666 g, 5.124 mmol). After 5 minutes, 2-dimethylaminoethanol (3.806 g, 4.291 mL, 42.70 mmol) and cesium carbonate (5 g) were added and the mixture was stirred at room temperature for 30 minutes, followed by heating to 50° C. for 30 minutes. After cooling to room temperature the mixture was filtered and the solid was rinsed with acetonitrile. The filtrate was concentrated in vacuo to an orange oil and purified by column chromatography using 4% MeOH/DCM as eluant. Solvent evaporations in vacuo afforded allyl 2-amino-5-(2-(dimethylamino)ethoxy)pyrazolo[1,5-a]pyrimidine-3-carboxylate as a light orange solid. (450 mg, 35% yield).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]12[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:14]3[C:15]1=[C:10]([CH:11]=[CH:12][CH:13]=3)[NH:9][C:8](=[O:25])[CH2:7]2)C.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[O:25]=[C:8]1[CH2:7][C:6]2([CH2:5][CH:4]=[O:3])[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C:14]3[C:15]2=[C:10]([CH:11]=[CH:12][CH:13]=3)[NH:9]1
Reactant: CCOC(=O)CC12CC(=O)Nc3cccc(c31)N(C(=O)OC(C)(C)C)C2
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2(CC=O)CC(=O)Nc3cccc1c32
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 2a-(2-ethoxy-2-oxoethyl)-4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-carboxylate, enantiomer A, from Step A (219 mg, 0.607 mmol) in CH2Cl2 (5 mL) at −78° C. was added DIBAL-H (1 M in CH2Cl2, 0.8 mL, 0.8 mmol) dropwise. After 1 h, DIBAL-H (1 M in CH2Cl2, 0.54 mL, 0.54 mmol) was added dropwise, and after an additional 1 h, more DIBAL-H (1 M in CH2Cl2, 0.65 mL, 0.65 mmol) was added dropwise. The mixture was stirred at −78° C. for 1 h, then quenched by addition of cold MeOH (1 mL), then acetone (1 mL), then saturated aqueous potassium sodium tartrate (10 mL). The mixture was allowed to warm to ambient temperature and was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=317 (M+1).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23]C(C)(C)C)=O)[CH2:17][CH2:16]1)=[O:7].C(O)(C(F)(F)F)=O.[NH:37]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@@H:38](C(O)=O)[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][C@@H:38]([NH:37][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:21](=[O:23])[N:18]2[CH2:17][CH2:16][CH:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]3[CH:3]=[CH:4][NH:5][C:6]3=[O:7])[CH2:20][CH2:19]2)=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: COC(CNC(=O)Nc1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1)OC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2-n2cc[nH]c2=O)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 17 (Step b) using tert-butyl 4-(2-{[(2,2-dimethoxyethyl)amino]carbonylamino}phenyl)piperidine-carboxylate (Step a) (0.742 g, 1.82 mmol) and a 50% aqueous TFA soln (20 mL) followed by Boc-p-Cl-D-PheOH (Advanced ChemTech) (0.545 g, 1.82 mmol), EDC (Advanced ChemTech) (0.523 g, 2.73 mmol), HOBT (Novabiochem) (0.246 g, 1.82 mmol) and TFA (Aldrich) (0.25 mL, 1.82 mmol) in CH2Cl2 (10 mL). Purification by silica gel chromatography (100% EtOAc then 1:9 MeOH:EtOAc) provided the title compound as a white solid (0.675 g). MS (ESI, pos. ion) m/z: 525 (M+1). Calc'd for C28H33ClN4O4: 524.22.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.C([Li])CCC.CN([CH:19]=[O:20])C.Cl>C(OCC)C.O.C(O)(=O)C>[S:4]1[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:2]([CH:19]=[O:20])=[CH:3]1
Reactant: CN(C)C=O
Reactant: Brc1csc2ccncc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1csc2ccncc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 2.14 g of 3-bromothieno[3,2-c]pyridine prepared as described above was added 150 ml of dry diethyl ether. The solution was stirred at room temperature for 15 minutes after which the temperature was gradually reduced to -70° C. and 6.5 ml of n-butyl lithium (1.6 molar) was added. The mixture was stirred for 30 minutes at -70° C. at which time a solution of 0.8 ml DMF in 20 ml of diethyl ether was added. This mixture was then stirred for an additional 1 hour and then allowed to warm to 0° C. at which time 3 ml of glacial acetic acid was added. The ether was removed via vacuum resulting in an oil which was taken up in approximately 400 ml of a mixture of 1N hydrochloric acid and water (pH adjusted to 1.5). This mixture was extracted with methylene chloride and the extract discarded. The pH of the mixture was adjusted to pH 11 and extracted a second time with methylene chloride. The extract was dried over magnesium sulfate and reduced to an oil via vacuum. The oil was taken up in hexane resulting in the formation of crystals of the desired subtitle intermediate which were collected and used as described below.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:19].[C:28](Cl)(=[O:30])[CH3:29].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[NH:1]([C:2]1[CH:3]=[C:4]([C:20]2[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:19])[C:28]([CH3:29])=[O:30]
Reactant: CC(=O)Cl
Reactant: COC(=O)CCN1CCN(c2ccc(-c3ccc(C#N)cc3)cc2N)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN1CCN(c2ccc(-c3ccc(C#N)cc3)cc2NC(C)=O)C1=O

Procedure:
Prepared from 1-(3-amino-4'-cyano-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one and acetylchloride in methylene chloride at ambient temperature using ethyl-diisopropylamine.
Reaction SMILES: Br[CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[I:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[I:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCCCCCCCC(C)Br
Reactant: Oc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCCCC(C)Oc1cccc(I)c1
Temperature: 75 °C
Reaction time: 14 h
Yield: 33.3 %

Procedure:
To a stirred solution of ethyl 10-bromoundecanoate (9.7 g, 33.0 mmol) in dry DMF (66 ml) was added 3-iodophenol (7.99 g, 36.3 mmol) and potassium carbonate (5.02 g, 37.6 mmol). The reaction was immersed in an oil bath which was warmed to 75° C. over 0.5 hr. After stirring for 14 hrs under an N2 atmosphere, the oil bath temperature was increased to 85° C. After stirring for an additional 4 hrs at 85° C., the reaction was allowed to cool, diluted with DMF (200 ml), filtered through a pad of celite and evaporated in vacuo. The resulting residue was taken up in ether (500 ml). The organic phase was washed with water (100 ml), 1M aqueous sodium hydroxide (100 ml), water (2×100 ml) and brine (100 ml), dried (Na2SO4), filtered and evaporated in vacuo to provide crude ethyl 10-(3-iodophenoxy)-undecanoate which was contaminated with olefinic esters. Flash column chromatography (silica, 1-2%; EtOAc in hexanes) provide ethyl 10-(3-iodophenoxy)-undecanoate as a clear oil (4.75 g, 33.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[NH:11][NH:10][C:9]2=[O:19])=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C(Cl)(Cl)Cl>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([N:11]2[CH:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:9](=[O:19])[NH:10]2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C1NNC(c2ccncc2)C1c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(N2NC(=O)C(c3ccc(Cl)cc3)C2c2ccncc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-Chloro-phenyl)-5-pyridin-4-yl-pyrazolidin-3-one 0.86 g and 4-Oxo-piperidine-1-carboxylic acid tert-butyl ester 0.75 g in chloroform 35 mL was added sodium triacetoxy boron hydride 0.75 g at 0° C., the reaction was warmed up to room temperature over two hours before heated to 50° C. for another two hours. The reaction was quenched with water 25 mL at 0° C., and the organic layer was collected, filtered, dried over MgSO4, concentrated to a yellow solid 0.42 g for being directly used for next step. MS (ES+): 457 (M+H)+.
Reaction SMILES: [C:1]1(=[CH:7][C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)=[CH:15][N:14]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[C:11]3=[N:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)=[CH:15][N:14]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[C:11]3=[N:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(C=C4CCCCC4)cc23)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(CC4CCCCC4)cc23)cn1
Temperature: 25 °C
Reaction time: 30.5 h

Procedure:
A mixture of 96 (32 mg, 0.073 mmol) and Pd(OH)2 (1.0 mg, 7.3 μmol) in MeOH (2.0 mL) was stirred under H2 at r.t. for 30.5 h. The mixture was filtered through Celite and concentrated to afford 97, which was used in the next step without purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([F:9])[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:5]([F:15])[CH:4]=1)#[N:2].[ClH:16]>CO.O1CCCC1.[C].[Pd]>[ClH:16].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([F:15])[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:7]([F:9])[CH:8]=1
Reactant: CS(=O)(=O)Nc1c(F)cc(C#N)cc1F
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)Nc1c(F)cc(CN)cc1F
Yield: 80 %

Procedure:
A mixture of N-(4-cyano-2,6-difluorophenyl)methanesulfonamide (1.01 g, 4.35 mmol) in methanol (15 ml), tetrahydrofuran (15 ml) and 12 M aqueous solution of hydrogen chloride (5 ml) was hydrogenated over 10% palladium-carbon (250 mg) under ballon pressure for 3 h at ambient temperature. The catalyst was filtered through a pad of celite and the filter cake was washed with methanol. After the filtrate and washings were evaporated in vacuo, the residue was recrystallized from methanol and diisopropyl ether to give to furnish 953 mg (80% yield) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]([CH3:44])[C:17]([N:19]1[C@H:27]([C:28]([O:30]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:29])[CH2:26][C:21]2([S:25][CH2:24][CH2:23][S:22]2)[CH2:20]1)=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]([CH3:44])[C:17]([N:19]1[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][C:21]2([S:22][CH2:23][CH2:24][S:25]2)[CH2:20]1)=[O:18])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CC2(C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1)SCCS2
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Reaction time: 0.5 h

Procedure:
A solution of (S,S,S)-7-[2-[(1-ethoxycarbonyl-3-phenylpropyl)amino]-1-oxopropyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, diphenylmethyl ester (800 mg.) in a mixture of trifluoroacetic acid (15 ml.) and anisole (3 ml.) is stirred at 0° for 30 minutes. The solvent is removed at reduced pressure and the residue applied to an AG 50W-X2(H+) column. After washing with water, the column is eluted with aqueous pyridine. The fractions containing the product are combined and lyophilized to yield (S,S,S)-7-[2-[(1-ethoxycarbonyl-3-phenylpropyl)amino]-1-oxopropyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].NCC[C:13]1[N:17]=[CH:16][NH:15][CH:14]=1.C=O>O1CCOCC1>[NH:15]1[CH:14]=[CH:13][N:17]=[C:16]1[CH:5]([NH:6][CH2:7][CH2:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3])[CH3:4]
Reactant: CC(=O)c1cccnc1
Reactant: NCCc1c[nH]cn1
Agent: C=O
Solvent: C1COCCO1
Product: CC(NCCC(=O)c1cccnc1)c1ncc[nH]1

Procedure:
3-acetylpyridine (6.5 mg), histamine (6 mg), and paraformaldehyde (2 mg) were reacted in dioxane (0.1 ml) at 150° C. for 2 hours.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[NH:23]1[CH2:28][CH2:27][CH2:26][CH:25]([CH2:29][OH:30])[CH2:24]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([CH2:29][OH:30])[CH2:24]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: OCC1CCCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCCC(CO)C1
Temperature: 65 °C
Yield: 21.7 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), piperidin-3-ylmethanol (0.047 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0068 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol), and cesium carbonate (0.31 g, 0.95 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated to dryness. The residue was purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (23.5 mg, 22%). LCMS calculated for C17H20ClN2O2 (M+H)+: m/z=319.1; Found
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:3]=1.CC1(C)C(C)(C)OB([C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]([NH2:49])=[N:41][CH:40]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.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>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH2:17][CH2:18]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([C:39]1[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]([NH2:49])=[N:41][CH:40]=1)=[N:3][C:4]=2[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: Cn1c(CN2CCC(N3CCOCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC1(C)OB(c2cnc(N)c3ccccc23)OC1(C)C
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: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(CN2CCC(N3CCOCC3)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)c4ccccc34)nc21
Temperature: 100 °C
Reaction time: 18 h
Yield: 13.8 %

Procedure:
To a degassed suspension of 4-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)morpholine (84 mg, 0.19 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-amine (52 mg, 0.19 mmol), 2 M Na2CO3 aqueous solution (0.19 mL, 0.38 mmol) in toluene (3 mL) and ethanol (1 mL) was added Pd(PPh3)4 (11 mg, 0.010 mmol). The suspension was then stirred under nitrogen at 100° C. for 18 hours. The reaction mixture was then diluted with EtOAc and water. The aqueous layer was extracted three times with EtOAc. The combined organic extracts were washed with water, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (25% MeOH in DCM) to give 139 as a white solid (14.3 mg, 14%). LCMS: M+H+=544.3. 1H-NMR (400 MHz, DMSO-d6): δ 9.01 (d, 1H), 8.25 (d, 1H), 8.16 (s, 1H), 7.67 (t, 1H), 7.49 (t, 1H), 7.08 (s, 2H), 4.23 (s, br, 4H), 3.82 (s, 3H), 3.78 (m, 6H), 3.55 (m, 4H), 2.88 (m, 2H), 2.43 (m, 4H), 2.07 (m, 3H), 1.75 (m, 2H), 1.38 (m, 2H)