Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:10][CH2:11][N:12]([CH2:26][C:27]([OH:29])=[O:28])[CH2:13][CH2:14][N:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][C:17]([OH:19])=[O:18])[CH2:6][C:7]([OH:9])=O)([OH:3])=[O:2].N1C=CC=CC=1>C(OC(=O)C)(=O)C>[O:9]=[C:7]1[CH2:6][N:5]([CH2:10][CH2:11][N:12]([CH2:13][CH2:14][N:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][C:17]([OH:19])=[O:18])[CH2:26][C:27]([OH:29])=[O:28])[CH2:4][C:1](=[O:2])[O:3]1
Reactant: CCOC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)CN(CCN(CCN1CC(=O)OC(=O)C1)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 21.1 g (50 mmol) of N3,N6-bis-(carboxymethyl)-N9-(ethoxy-carbonylmethyl)-3,6,9-triazaundecanedioic acid in 250 ml of acetic anhydride is allowed to stir for three days at room temperature after the addition of 42.2 ml of pyridine. Then, the precipitate is suctioned off, washed three times with 50 ml of acetic anhydride each and then stirred for several hours with absolute diethyl ether. After suctioning off, washing with absolute diethyl ether and drying in a vacuum at 40° C., 18.0 g (=89% of theory) of a white powder with a melting point of 195-196° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:27]=2[C:28]([NH:30][CH2:31][CH3:32])=[O:29])[C:22]([Cl:38])=[CH:21][N:20]=1>>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:27]=2[C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(CC)C(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide to yield a yellow solid (6.3%). LCMS: m/z=525.19 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.11 (s, 1H), 7.49 (s, 1H), 7.35 (d, 1H, J=7.3 Hz), 7.24 (m, 3H), 7.14 (d, 1H, J=8.6 Hz), 7.02 (s, 1H), 3.70 (m, 2H), 3.43 (m, 2H), 2.26 (m, 2H), 2.06 (s, 2H), 1.32 (s, 6H), 1.28 (m, 3H), 1.18 (m, 3H).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([S:19][CH:20]([CH3:22])[CH3:21])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:23]C(OC(Cl)C)=O>C1(C)C=CC=CC=1>[ClH:23].[CH3:22][CH:20]([S:19][C:17]1[CH:16]=[N:15][C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[N:18]=1)[CH3:21]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC(C)Sc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Solvent: Cc1ccccc1
Product: CC(C)Sc1cnc2c(n1)OCCNC2
Product: Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 21 %

Procedure:
To a solution of 8-benzyl-3-[(1-methylethyl)sulfanyl]-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (111 mg) in toluene (3 mL) was added 1-chloroethyl chloroformate (0.042 mL), and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was cooled to room temperature, and concentrated. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→40% ethyl acetate/hexane). To the obtained oil was added methanol (3 mL), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, and concentrated. The obtained residue was purified by recrystallization (ethanol-diisopropyl ether) to give the title compound (19.2 mg, 21%) as pale-yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[CH:4][C:3]=1[CH2:16]Br.BrC1C(CBr)=CC([O:23][CH:24]2[CH2:29]CCC[O:25]2)=CC=1CBr.CN(C=O)C.CC([O-])=O.[K+]>C(Cl)Cl.O>[C:24]([O:25][CH2:16][C:3]1[CH:4]=[C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:13]=[C:14]([CH3:15])[C:2]=1[Br:1])(=[O:23])[CH3:29]
Reactant: Cc1cc(OC2CCCCO2)cc(CBr)c1Br
Reactant: BrCc1cc(OC2CCCCO2)cc(CBr)c1Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(OC2CCCCO2)cc(C)c1Br
Temperature: 60 °C
Yield: 52 %

Procedure:
Intermediates 2-(4-bromo-3-(bromomethyl)-5-methylphenoxy)tetrahydro-2H-pyran and 2-(4-bromo-3,5-bis(bromomethyl)phenoxy)tetrahydro-2H-pyran from above reaction was made into a solution with 33 mL of DMF. The reaction mixture was then treated with KOAc (6.95 g, 70.83 mmol) before heating to 60° C. for 2 hr. The reaction was worked-up with equal volumes of water and CH2Cl2 (1:1, 50 mL). The layers were separated and the water phase was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 2-bromo-3-methyl-5-(tetrahydro-2H-pyran-2-yloxy)benzyl acetate (2.24 g, two steps 52%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([NH:18][CH:19]2[CH2:29][CH2:28][C:22]3([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:21][CH2:20]2)=[N:5][C:6]([NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[NH:12][N:11]=2)=[N:7][CH:8]=1.[C:30]([CH2:32][C:33](O)=[O:34])#[N:31].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[C:4]([NH:18][CH:19]2[CH2:29][CH2:28][C:22]3([CH2:27][CH2:26][N:25]([C:33](=[O:34])[CH2:32][C:30]#[N:31])[CH2:24][CH2:23]3)[CH2:21][CH2:20]2)=[N:5][C:6]([NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[NH:12][N:11]=2)=[N:7][CH:8]=1
Reactant: Clc1cnc(Nc2cc(C3CC3)[nH]n2)nc1NC1CCC2(CCNCC2)CC1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCC(=O)N1CCC2(CCC(Nc3nc(Nc4cc(C5CC5)[nH]n4)ncc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36.9 %

Procedure:
To a solution of 5-chloro-N2-(5-cyclopropyl-1H-pyrazol-3-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine hydrochloride (270 mg, 0.6159 mmol) in a mixture of DCM and DMF (6 mL/2 mL) were added TEA (253.2 mg, 2.502 mmol), cyanoacetic acid (52.1 mg, 0.733 mmol), HOAT (124.8 mg, 0.9169 mmol) and EDCI (177.5 mg, 0.9259 mmol). The reaction mixture was stirred at rt for 1.5 h then quenched with water (30 mL), and extracted with DCM/MeOH (10/1, 80 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1). The crude product was recrystallized from MeOH (10 mL) to give the title compound as a white solid (106.6 mg, 36.91%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([C:11]#[N:12])[C:5]2=[CH:4][CH:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1>>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[CH:9]=[C:10]([C:11]#[N:12])[C:5]2=[CH:4][CH:3]=1
Reactant: N#Cc1c[nH]c2nc(Br)ccc12
Reactant: Fc1cccc(CBr)c1
Product: N#Cc1cn(Cc2cccc(F)c2)c2nc(Br)ccc12

Procedure:
The title compound was prepared as described in Example 28A using 6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile in place of 6-bromo-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile and using 1-(bromomethyl)-3-fluorobenzene in place of 4-(bromomethyl)tetrahydro-2H-pyran.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH2:2]1.CNC.CN(C)[P:18](N(C)C)N(C)C>>[N:1]12[P:18]3[N:9]([CH2:8][CH2:7][CH2:6][N:5]3[CH2:4][CH2:3][CH2:2]1)[CH2:10][CH2:11][CH2:12]2
Reactant: CN(C)P(N(C)C)N(C)C
Reactant: C1CNCCCNCCCNC1
Agent: CNC
Product: C1CN2CCCN3CCCN(C1)P23
Yield: 75.8 %

Procedure:
A mixture of 4.20 g of 1,5,9-triazacyclododecane and 4.00 g of hexamethylphosphorous triamide is heated at 100° C for about six hours, by which time evolution of dimethylamine is complete. Distillation under reduced pressure gives 3.70 g (76%) of 1,5,9-triaza-13-phosphatricyclo-[7.3.1.05,13 ]tridecane as a clear, colorless liquid which boils at 104°-135° C at 0.60 mm. The product solidifies at room temperature. Its infrared absorption spectrum (neat) shows absorptions at 3.5, 6.85, 7.01, 7.52, 7.73, 8.00, 8.27, 8.66, 8.90, 9.02, 9.36, 9.56, 10.27, 10.89, 11.42, 11.73, 11.97 and 14.7 μ. The mass spectrum shows an M+ ion at 199; measured mass, 199.1264; calc'd, 199.1238.
Reaction SMILES: Cl[C:2]1[N:14]=[C:13]([O:15][CH2:16][CH:17]([F:19])[F:18])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][CH2:7]C(F)F)=[O:5].[CH3:20][O-:21].[Na+].O>C1COCC1>[F:18][CH:17]([F:19])[CH2:16][O:15][C:13]1[CH:12]=[CH:11][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:21][CH3:20])[N:14]=1
Reactant: C[O-]
Reactant: O=C(OCC(F)F)c1ccc(OCC(F)F)nc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCC(F)F)nc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.4 %

Procedure:
To a stirred solution of 2,2-difluoroethyl 2-chloro-6-(2,2-difluoroethoxy)nicotinate (2.9 g, 9.8 mmol, Step-1) in THF (35 mL) is added sodium methoxide (1.58 g, 29.2 mmol) at 0° C. Then the mixture is stirred at rt for 15 hours. The mixture is poured into water and extracted with DCM (10 mL×3). The combined organic layer is washed with water, brine, and dried over sodium sulfate. The organic solvent is removed under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (4:1 to 1:4) to give 615 mg (26% yield) of the title compound as white solid.
Reaction SMILES: C([Li])CCC.[I:6]I.Br[C:9]1[CH:10]=[C:11]([Cl:16])[C:12]([Cl:15])=[N:13][CH:14]=1>C(OCC)C.CCCCCC>[Cl:15][C:12]1[C:11]([Cl:16])=[CH:10][C:9]([I:6])=[CH:14][N:13]=1
Reactant: II
Reactant: Clc1cc(Br)cnc1Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Clc1cc(I)cnc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In one embodiment of the present invention, 5-bromo-2,3-dichloropyridine is dissolved in ethyl ether and cooled to about -78° C. A slight excess molar quantity of n-butyl lithium, dissolved in hexane, is slowly added to the reaction mixture with mild agitation. After about 0.5 hour of stirring, a slight excess molar quantity of I2, dissolved in ethyl ether, is added to reaction mixture with mild agitation. After about 0.5 hour of stirring, the reaction mixture is allowed to warm to room temperature and the 2,3-dichloro-5-iodopyridine is isolated employing standard separatory and purification techniques.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([O:10][CH3:11])=[CH:4][N:3]=1.[O:12]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O>[CH3:11][O:10][C:5]1[C:6](=[O:9])[N:7]([CH3:8])[C:2]([C:22]2[CH:23]=[CH:24][C:19]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:20][CH:21]=2)=[N:3][CH:4]=1
Reactant: COc1cnc(Cl)n(C)c1=O
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cnc(-c2ccc(Oc3ccccc3)cc2)n(C)c1=O
Temperature: 120 °C
Yield: 100.3 %

Procedure:
To a solution of 750 mg (4.30 mmol) 2-chloro-5-methoxy-3-methylpyrimidin-4(3H)-one in 20 ml THF was added 314 mg (0.430 mmol) 1,1′-bis(diphenylphosphino)ferrocene-palladium(H)dichloride dichloromethane adduct, 1.83 g (8.59 mmol) 4-phenoxyphenylboronic acid, and 4.30 ml (4.30 mmol) 1 M aq Cs2CO3. The reaction mixture was heated to 120° C. for 15 min in the microwave, then diluted with 10 ml water, extracted with 50 ml EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo to give 1.33 g (100% yield) of crude 5-methoxy-3-methyl-2-(4-phenoxyphenyl)pyrimidin-4(3H)-one.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([O:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:22]=2)[NH:19][C:18]([C:30]([NH2:32])=O)=[CH:17]3)=[CH:9][CH:8]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([O:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:22]=2)[NH:19][C:18]([C:30](=[S:42])[NH2:32])=[CH:17]3)=[CH:9][CH:8]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCCOCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cn1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=S)cc3c2)cn1
Yield: 96.5 %

Procedure:
To a solution of 5-({6-[(2-methoxyethoxy)methyl]pyridin-3-yl}oxy)-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxamide (1.1 g) in tetrahydrofuran (20 mL) was added a Lawesson's reagent (1.1 g), and the mixture was stirred with heating under reflux for 1 hr. The reaction mixture was cooled, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (1.1 g, yield 96%) as a yellow amorphous solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40](O)=[O:41])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28](Cl)=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:46].[CH3:47][S:48]([CH2:51][CH2:52][NH:53][CH3:54])(=[O:50])=[O:49]>>[CH3:47][S:48]([CH2:51][CH2:52][N:53]([CH3:54])[C:40]([CH:37]1[CH2:38][CH2:39][N:34]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:46])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=2[O:43][CH2:44][CH3:45])=[O:33])[CH2:35][CH2:36]1)=[O:41])(=[O:50])=[O:49]
Reactant: Cl
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)O)CC1
Reactant: CNCCS(C)(=O)=O
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)N(C)CCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 163, 1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidine-4-carboxylic acid was coupled with (2-methanesulfonylethyl)-methylamine hydrochloride (Array) to give the title compound. HR-MS (ES, m/z) calculated for C39H50Cl2N5O5S [(M+H)+] 770.2904, observed 770.2905.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:38][CH:39]([CH2:49][C:50]1[CH:51]=[CH:52][C:53]2[O:57][CH2:56][C:55]([CH3:59])([CH3:58])[C:54]=2[CH:60]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41]>CN(C)C=O.C(OCC)(=O)C>[Cl:48][C:44]1[CH:43]=[C:42]([CH:40]([OH:41])[CH:39]([NH:38][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)=[O:14])[CH2:49][C:50]2[CH:51]=[CH:52][C:53]3[O:57][CH2:56][C:55]([CH3:59])([CH3:58])[C:54]=3[CH:60]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: CC1(C)COc2ccc(CC(N)C(O)c3cccc(Cl)c3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)COc2ccc(CC(NC(=O)c3ccc(F)c4ccccc34)C(O)c3cccc(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of 4-fluoronaphthalene-1-carboxylic acid (242 mg, 1.27 mmol) in N,N-dimethylformamide (10 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (243 mg, 1.27 mmol) and 1-hydroxybenzotriazole monohydrate (195 mg, 1.27 mmol), and (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1-propanol (0.40 g, 1.21 mmol) was finally added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered using a glass filter filled with silica gel. The filtrate was washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-2-hydroxyethyl}-4-fluoro-1-naphthamide (383 mg, 68%) as colorless crystals.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-:26].[Na+].[CH2:28]([OH:30])[CH3:29]>C1COCC1>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:5]3[CH2:9][CH2:8][CH:29]([C:28]([OH:26])=[O:30])[CH2:2][CH2:1]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [OH-]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: CCO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)N3CCC(C(=O)O)CC3)cs2)c1-c1ccc(F)cc1
Yield: 83 %

Procedure:
A mixed solution of 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid (95 mg, 0.19 mmol) and 1N aqueous sodium hydroxide solution (0.286 mL, 0.29 mmol) in ethanol (2 mL) and THF (2 mL) was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and water and 1N hydrochloric acid were added to the residue. After extraction with ethyl acetate, washing with water and saturated brine and drying, the solvent was evaporated under reduced pressure to give the title compound (74 mg, 0.157 mmol, 83%) as a white powder.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([NH:13][C@H:14]([CH3:17])[CH2:15][OH:16])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:16][CH2:15][C@H:14]([NH:13][C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH3:17])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
Methanesulfonyl chloride (0.64 mL) was added dropwise to an ice-cooled mixture of (R)-(+)-2-(tert-butoxycarbonylamino)-propanol (1.31 g) and triethylamine (1.6 mL) in methylene chloride (20 mL) with stirring, and the mixture was stirred at that temperature for 1 hr. The reaction mixture was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (1.93 g).
Reaction SMILES: [CH2:1]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[C:2]([CH3:4])=[O:3].C[C:15]([CH3:22])([C:19]([O-:21])=O)C([O-])=O.[Na+].[Na+].[C:25](OC(=O)CC)(=[O:28])[CH2:26]C.Cl>CO>[C:19]([CH:4]1[C:2](=[O:3])[CH2:1][C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][CH2:6]2)[CH2:26][C:25]1=[O:28])(=[O:21])[CH2:15][CH3:22]
Reactant: CCC(=O)OC(=O)CC
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Reactant: CC(=O)CC1C=Cc2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCC(=O)C1C(=O)CC2(CCc3ccccc32)CC1=O
Temperature: 60 °C

Procedure:
1-Acetonylindene (2.4 g) was added to a solution of sodium dimethylmalonate (5.3 equiv) in anhydrous methanol (80 ml) and the mixture was stirred and heated at reflux for 12 hr. The solvent was evaporated and the residue was azeotroped with toluene. The dry residue was dissolved in anhydrous dimethylformamide (80 ml) at 60° C. Propionic anhydride (5.3 equiv) was added and the mixture was stirred and heated at reflux for 0.5 hr. The cooled mixture was poured into a dilute aqueous hydrochloric acid solution which was then extracted with diethyl ether. The organic fraction was evaporated and the residue was heated at reflux with potassium hydroxide (5 g) in water (80 ml) for 4 hr. The cooled mixture was extracted with diethyl ether. The aqueous fraction was heated to 60° C. and was acidified by dropwise addition of a dilute aqueous hydrochloric acid solution. The cooled mixture was extracted with diethyl ether. The dried (MgSO4) organic fraction was evaporated and the residue was purified by column chromatography over silica with dichloromethane elution to give 4-propionylspiro[cyclohexane-1,1'-indan]-3,5-dione as a pale yellow oil. Pmr spectrum (CDCl3 ; δ in ppm): 1.17 (3H, t); 2.03 (2H, t); 2.64-3.24 (8H, m); 7.21-7.25 (4H, m); 18.27 (1H, s). 4-Butyrylspiro[cyclohexane-1,1'-indan]-3,5-dione was similarly prepared from 1-acetonylideneindane, sodium dimethyl malonate and n-butyric anhydride and was obtained as a pale yellow oil. Pmr spectrum (CDCl3 ; δ in ppm): 1.00 (3H, t); 1.70 (2H, m); 2.02 (2H, t); 2.62-3.14 (8H, m); 7.20-7.25 (4H, m); 18.33 (1H, s).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[N:12]=2)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:6]=1)=[O:4].[O:33]=[C:34]([N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:35][C:36]#[N:37].N1CCCCC1>CO>[CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[C:35]([C:34]([N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:33])[C:36]#[N:37])=[CH:17][CH:16]=3)[N:12]=2)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:28])[CH3:29])[CH:6]=1)=[O:4]
Reactant: N#CCC(=O)N1CCCCC1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCCCC4)cc3)nc12
Reaction time: 5 h
Yield: 59.6 %

Procedure:
To a 20 ml vial 4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxymethyl)-pyrrolo[2,3-b]pyrazin-2-yl]amino]benzaldehyde (35 mg, 0.0800 mmol), 3-oxo-3-(1-piperidyl)propanenitrile (18.01 mg, 0.1200 mmol), piperdine (0.02 ml, 0.15 mmol) and 3-oxo-3-(1-piperidyl)propanenitrile (18.01 mg, 0.12 mmol), were taken in methanol (5 ml). To this reaction mixture, piperdine (0.02 ml, 0.15 mmol) was added drop wise at RT. After completion of the addition, the reaction mixture was stirred for 5 hrs. Ethanol was evaporated, the residue was loaded on silica gel column and elution with CH2Cl2 to MeOH 0-2, 3% yielded 28 mg of 3-[4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazin-2-yl]amino]phenyl]-2-(piperidine-1-carbonyl)prop-2-enenitrile.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH2:15]([C:22]1[S:26][N:25]=[C:24]([C:27](O)=[O:28])[N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:15]([C:22]1[S:26][N:25]=[C:24]([C:27]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=3)[NH:8][CH:7]=2)=[O:28])[N:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1nsc(Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1nsc(Cc2ccccc2)n1

Procedure:
The 5-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1,2,4-thiadiazole-3-carboxamide is prepared following method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride, 5-benzyl-1,2,4-thiadiazole-3-carboxylic acid (which can be prepared by procedures known to the skilled in the art), HATU and N,N-diisopropylethylamine in DMF.