Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH3:16][O:17][C:18](=[O:46])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]OS(C)(=O)=O)=[C:25](/[CH:40]=[CH:41]/[C:42]([O:44]C)=[O:43])[CH:24]=1>>[CH3:16][O:17][C:18](=[O:46])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])=[C:25](/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43])[CH:24]=1
Reactant: COC(=O)/C=C/c1cc(OCCCC(=O)OC)ccc1CCCCCCOS(C)(=O)=O
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCCc2ccc(OCCCC(=O)OC)cc2/C=C/C(=O)O)ccc2c1OCCC2=O
Yield: 95 %

Procedure:
Using the procedure of example 11 and starting with 0.26 g (1.3 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.76 g (1.3 mmol) of (E)-4-[3-(3-methoxy-3-oxo-1-propenyl)-4-[6-[(methylsulfonyl)oxy]hexyl]phenoxy]butanoic acid methyl ester (from example 113), (E)-4-[3-(2-carboxyethenyl)-4-[6[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]hexyl]phenoxy]butanoic acid methyl ester was obtained in 95% yield (0.36g) as a colorless oil which crystallized on standing. Recrystallization from ethyl acetate-hexane gave 0.51 g (69%) of a colorless solid, mp 65°-66° C. A 0.2 g (0.35 mmol) sample of diester prepared in this way was saponified with 2 mL of 3N aqueous lithium hydroxide in 10 mL of tetrahydrofuran, at room temperature, for 22 hr. Work-up as in example 4 gave a crude acid product which was purified by chromatography on silica gel (toluene-ethyl acetate containing 2% acetic acid) and recrystallization from acetonitrile. There was obtained 0.1 g (53%) of (E)-4-[3-(2-carboxyethenyl)-4-[6-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]hexyl]phenoxy]butanoic acid as an off-white solid mp 140°-143° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N+:9]2[O-])=[N:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=[O:20])=CC=1.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[NH:9]2)=[N:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [O-][n+]1cccc2ncc(F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1ccc2ncc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
To a solution of 60 mg of 7-fluoro-1,5-naphthyridine 1-oxide in 1.6 mL of chloroform, 84 mg of p-toluenesulfonyl chloride, 171 mg of potassium carbonate and 0.5 mL of water were added, and the mixture was stirred at room temperature overnight. The solid was filtered off, and purified by silica gel column chromatography using silica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and an eluent of chloroform:methanol=10:1 to obtain 14 mg of 7-fluoro-1,5-naphthyridin-2(1H)-one as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH:27]([C:31](O)=[O:32])[CH2:26]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:31]([CH:27]3[CH2:28][CH2:29][CH2:30][O:25][CH2:26]3)=[O:32])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCCOC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCCOC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(tetrahydro-pyran-3-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using rac-tetrahydro-pyran-3-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 461.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](Cl)=[N:6][OH:7].[CH3:12][O:13][C:14](=[O:19])[CH2:15][C:16]([CH3:18])=O.C[O-].[Na+]>CO>[CH3:12][O:13][C:14]([C:15]1[C:5]([C:4]2[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)=[N:6][O:7][C:16]=1[CH3:18])=[O:19]
Reactant: ON=C(Cl)c1cccc(F)c1
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2cccc(F)c2)noc1C
Yield: 69.7 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), 3-fluoro-N-hydroxybenzimidoyl chloride (8.00 g, 46.09 mmol), methylacetoacetate (10.07 g, 92.18 mmol) and sodium methoxide (7.47 g, 138.27 mmol), a white solid required compound (7.60 g, 32.14 mmol, 70%) was obtained.
Reaction SMILES: C([NH:8][C:9]([N:18]1[CH:22]=[CH:21][CH:20]=N1)=[N:10]C(OC(C)(C)C)=O)(OC(C)(C)C)=O.NCCC[CH2:27][CH2:28][O:29][C:30]1[C:31]([O:50][CH3:51])=[CH:32][CH:33]=[C:34]2[C:39]=1[O:38][C:37](=[O:40])[CH:36]=[C:35]2[NH:41][C:42]1[C:47]([Cl:48])=[CH:46][N:45]=[CH:44][C:43]=1[Cl:49].FC(F)(F)C(O)=O>ClCCl>[Cl:49][C:43]1[CH:44]=[N:45][CH:46]=[C:47]([Cl:48])[C:42]=1[NH:41][C:35]1[C:34]2[C:39](=[C:30]([O:29][CH2:28][CH2:27][CH2:20][CH2:21][CH2:22][NH:18][C:9]([NH2:8])=[NH:10])[C:31]([O:50][CH3:51])=[CH:32][CH:33]=2)[O:38][C:37](=[O:40])[CH:36]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCN
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCNC(=N)N
Reaction time: 0.5 h

Procedure:
N,N′-Di-Boc-1H-pyrazole-1-carboxamidine (40 mg, 0.13 mmol) was added to a mixture of 8-(5-aminopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (40 mg, 0.09 mmol, Example 68) and dichloromethane (3 mL). After stirring for 30 min, trifluoroacetic acid (0.3 mL) was added. After an additional 19 h, the reaction was concentrated and purified by reverse-phase HPLC (1:9→3:2; acetonitrile:water) to give to give 1-(5-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)pentyl)guanidine: 1H NMR (400 MHz, DMSO-d6; HCl salt): δ 9.60 (s, 1H), 8.82 (s, 2H), 7.98 (d, 1H), 7.57 (t, 1H), 7.50-6.70 (br, 4H), 7.21 (d, 1H), 4.63 (s, 1H), 3.98 (t, 2H), 3.92 (s, 3H), 3.11 (m, 2H), 1.70 (m, 2H), 1.52 (m, 4H); MS (ESI): 479.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)=[CH:16][CH:15]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][CH2:36][CH2:37][N:38]3[CH2:41][CH2:42][CH2:43][OH:44])=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:45][S:46](Cl)(=[O:48])=[O:47]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH:26]3[CH2:27][CH2:28]3)=[CH:18][CH:19]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][CH2:36][CH2:37][N:38]3[CH2:41][CH2:42][CH2:43][O:44][S:46]([CH3:45])(=[O:48])=[O:47])=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC3CC3)cc2)[C@@H](OCc2ccc3c(c2)N(CCCO)CCC3)C1
Reactant: CS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC3CC3)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOS(C)(=O)=O)CCC3)C1

Procedure:
In analogy to the procedure described in example 8(b), the (3R,4R)-4-[4-(3-cyclopropylmethoxy-propoxy)-phenyl]-3-[1-(3-hydroxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester was reacted with methanesulfonyl chloride to yield the crude (3R,4R)-4-[4-(3-cyclopropylmethoxy-propoxy)-phenyl]-3-[1-(3-methanesulfonyloxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester which was used without further purification or characterization.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].Cl.[Cl:11][CH2:12][C:13]1[NH:14][CH2:15][CH2:16][N:17]=1>C(O)C>[ClH:11].[NH:17]1[CH2:16][CH2:15][N:14]=[C:13]1[CH2:12][S:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1
Reactant: ClCC1=NCCN1
Reactant: Sc1nnc(S)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Sc1nnc(SCC2=NCCN2)s1
Yield: 52.2 %

Procedure:
In 30 ml of ethanol was suspended 2.25 g of 2,5-dimercapto-1,3,4-thiadiazole, and 30 ml of 1N-sodium hydroxide solution was added to the suspension under ice-cooling and stirring. To the mixture was further added 2.33 g of 2-(chloromethyl)imidazoline hydrochloride, and the mixture was stirred at room temperature for 90 minutes and concentrated under reduced pressure. The concentrate was adjusted to pH 4.8 and washed with ethyl acetate. The aqueous layer was concentrated and subjected to a column chromatography on XAD-II (300 ml), being washed with water and eluted with 10% aqueous ethanol. The eluate was evaporated to dryness under reduced pressure. To the residue were added 50 ml of ethanol and 5 ml of conc hydrochloric acid, and the resultant was stirred. The precipitating crystals were collected by filtration and washed with ethanol to give 2.10 g of 2-(2-imidazolin-2-yl)methylthio-5-mercapto-1,3,4-thiadiazole hydrochloride as colorless crystals (mp 204°-209° C. decomp.).
Reaction SMILES: Cl.Cl[CH:3]1[CH2:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:6]=2[N:5]([CH3:22])[CH2:4]1.O.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:21][C:18]1[CH:19]=[CH:20][C:6]2[N:5]([CH3:22])[CH:3]([CH2:4][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:7]=2[CH:17]=1
Reactant: C1CCNCC1
Reactant: CN1CC(Cl)CN=C(c2ccccc2)c2cc(Cl)ccc21
Agent: Cl
Solvent: O
Product: CN1c2ccc(Cl)cc2C(c2ccccc2)=NCC1CN1CCCCC1

Procedure:
100 mg of 3,8-dichloro-1-methyl-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine hydrochloride is heated in 10 ml piperidine under reflux for 24 hours. For processing the mass was poured into water, extracted with chloroform and the chloroform was subsequently distilled off in a vacuum. The product was recrystallized from ether and there was obtained 7-chloro-1-methyl-2-piperidinomethyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine which also was identical with the same material obtained in Examples 4 and 6 of application Ser. No. 355 986 directly by heating acyldiamines with phosphoroxychloride and subsequent reaction with piperidine; m.p. 143°-145° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[N:14][CH:13]=3)[CH2:9][C:8](=[O:18])[NH:7][C:6]=2[CH:19]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O>>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[N:14][CH:13]=3)[CH2:9][C:8](=[O:18])[NH:7][C:6]=2[CH:19]=1
Reactant: OB(O)c1cccs1
Reactant: O=C1CC(c2ccnnc2)=Nc2ccc(Br)cc2N1
Product: O=C1CC(c2ccnnc2)=Nc2ccc(-c3cccs3)cc2N1

Procedure:
The title compound was prepared from 8-bromo-4-(pyridazin-4-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one (Example 1; 1 mmol) and commercial available thiophene-2-boronic acid (CAS-No: 6165-68-0)) (1.5 mmol) according to the general procedure G. Obtained as a yellow solid (51%), MS (EI) 321 [(M+1)+].
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[O:8][C:4]=2[CH:3]=1.Cl.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[N:31]([C:28]4[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=4)[N:32]=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1nc2ccc(F)cc2o1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2nc3ccc(F)cc3o2)cc1

Procedure:
The procedure of Example 9 was repeated using 1-(6-fluorobenzoxazol-2-yl)-4,4,4-trifluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 6-fluoro-2-[1-(4-methylsulfonylphenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzoxazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1/[CH:21]=[CH:22]/[C:23](O)=[O:24].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCOCC>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1/[CH:21]=[CH:22]/[C:23]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]
Reactant: COc1cccc(-c2ccc3c(/C=C/C(=O)O)c(OC)ccc3c2)c1
Reactant: Nc1ccccc1
Solvent: CCOCC
Product: COc1cccc(-c2ccc3c(/C=C/C(=O)Nc4ccccc4)c(OC)ccc3c2)c1

Procedure:
The compound was prepared by reaction of (E)-3-(2-methoxy-6-(3-methoxyphenyl)naphthalene-1-yl)acrylic acid (200 mg, 0.60 mmol, 1 eq) with aniline (1 eq) according to method D. Characterization of this compound was not effected. The raw product was directly employed for ether cleavage.
Reaction SMILES: [CH:1]([C:5]([CH3:13])([CH:9]([CH3:12])[CH2:10][CH3:11])[C:6](Cl)=[O:7])([CH2:3][CH3:4])[CH3:2].[CH2:14]([CH2:16][NH2:17])[OH:15]>C1C=CC=CC=1>[OH:15][CH2:14][CH2:16][NH:17][C:6](=[O:7])[C:5]([CH:9]([CH2:10][CH3:11])[CH3:12])([CH3:13])[CH:1]([CH3:2])[CH2:3][CH3:4]
Reactant: NCCO
Reactant: CCC(C)C(C)(C(=O)Cl)C(C)CC
Solvent: c1ccccc1
Product: CCC(C)C(C)(C(=O)NCCO)C(C)CC

Procedure:
A solution of 2-sec-butyl-2,3-dimethylpentanoyl chloride (2.0 g) in benzene (10 ml) was added to a stirred solution of ethanolamine (2.0 g) in benzene (100 ml). After 16 hours the benzene solution was washed with dilute hydrochloric acid and water, dried (MgSO4) and concentrated to give a pale yellow syrup. Distillation of this syrup gave N-(2-hydroxyethyl)-2-sec-butyl-2,3-dimethylpentanamide bp. 125°-130°/0.3 mm which slowly solidified on standing.
Reaction SMILES: [F:1][C:2](I)([F:19])[C:3]([F:18])([F:17])[C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].OCS([O-])=O.[Na+].[C:27]1([S:33]SC2C=CC=CC=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O.O>[F:1][C:2]([S:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([F:19])[C:3]([F:18])([F:17])[C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: c1ccc(SSc2ccccc2)cc1
Agent: O=S([O-])CO
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Sc1ccccc1
Yield: 40 %

Procedure:
Perfluorohexyl iodide (4.5 g), sodium hydroxymethanesulphinate (4 g) and phenyl disulphide (2.2 g) in dimethylformamide (10 cc) and water (0.5 cc) are stirred for 12 hours. After the usual treatment, phenyl perfluorohexyl sulphide is obtained in 40% yield.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:21]=[CH:20][C:19]([NH:22]C(=O)OCC5C=CC=CC=5)=[CH:18][C:17]=4[F:33])=[CH:11][N:10]3[CH:34]=2)=[O:5])[CH2:3][CH2:2]1.[OH-].[Ba+2].[OH-].Cl>COCCOC>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:12]2[CH:13]=[CH:14][C:9]3[N:10]([CH:34]=[C:7]([NH:6][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[N:8]=3)[CH:11]=2)=[C:17]([F:33])[CH:18]=1
Reactant: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1)OCc1ccccc1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Product: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
To a suspension of benzyl [4-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-a]pyridin-6-yl}oxy)-3-fluorophenyl]carbamate (18.0 g, 39.1 mmol) in 1,2-dimethoxyethane (360 mL) was added 0.15 mol/L aqueous barium hydroxide solution (240 mL), and the mixture was stirred at 90° C. for 16 hr. After cooling to room temperature, the reaction mixture was adjusted to about pH 8 with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate and collected by filtration to give the title compound (9.1 g, 71%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH2:28][C:29]#[N:30])[CH2:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][C:39]2=[O:44])=[CH:34][CH:33]=1>>[O:44]=[C:39]1[N:38]([C:35]2[CH:34]=[CH:33][C:32]([NH:31][C:2]3[N:7]=[C:6]([C:8]4[CH:9]=[N:10][N:11]([CH:13]([CH2:14][CH:15]5[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]5)[CH2:28][C:29]#[N:30])[CH:12]=4)[CH:5]=[CH:4][N:3]=3)=[CH:37][CH:36]=2)[CH2:43][CH2:42][O:41][CH2:40]1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(CC#N)n2cc(-c3ccnc(Cl)n3)cn2)CC1
Product: N#CCC(CC1CCNCC1)n1cc(-c2ccnc(Nc3ccc(N4CCOCC4=O)cc3)n2)cn1

Procedure:
This compound was prepared as a racemic mixture, by coupling of tert-butyl 4-(2-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyanopropylpiperidine-1-carboxylate (from example 1, step 4) with 4-(4-aminophenyl)-3-morpholinone (from Affinitis Pharma) according to the procedure described in example 1, step 6. LCMS (M+H) 487.1.
Reaction SMILES: CN([CH:4]=[O:5])C.CS(C)=O.[C:10]1(C)[C:11](C)=[CH:12][CH:13]=[CH:14][CH:15]=1>>[C:15]1([O:5][C:4]2[CH:12]=[CH:11][CH:10]=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccccc1C
Reactant: CN(C)C=O
Solvent: CS(C)=O
Product: c1ccc(Oc2ccccc2)cc1

Procedure:
Method G illustrates still another means for obtaining intermediate XIII. In this method, substituted propriolate ester XVI is reacted with amidoxime XVII in a suitable solvent (e.g., alcohol, acetonitrile, THF, dimethylsulfoxide (DMSO), acetone, DMF) at about 0° C. to the reflux temperature of the solvent for about 1-48 hours to obtain olefin XVIII wherein when R1 =H, a mixture of cis and trans isomers is obtained, and when R1 =alkyl or aryl, a mixture of E and Z isomers is obtained. Further treatment of olefin XVIII in solvents such as DMF, DMSO, diphenylether, xylene, and the like, at 0° C. to the reflux temperature of the solvent for about 1-48 hours affords intermediate XIII, preferably for 1 hour in diphenylether at 180°-200° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:53]([O:55][C:56](=[O:77])[CH:57]=[CH:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]([CH3:68])([CH3:67])[CH3:66])=[CH:61][C:60]=1OS(C(F)(F)F)(=O)=O)[CH3:54].[CH3:78][N:79]1[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:53]([O:55][C:56](=[O:77])[CH:57]=[CH:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]([CH3:68])([CH3:67])[CH3:66])=[CH:61][C:60]=1[N:82]1[CH2:83][CH2:84][N:79]([CH3:78])[CH2:80][CH2:81]1)[CH3:54]
Reactant: CCOC(=O)C=Cc1ccc(C(C)(C)C)cc1OS(=O)(=O)C(F)(F)F
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(C(C)(C)C)cc1N1CCN(C)CC1
Reaction time: 0.08 h
Yield: 73.2 %

Procedure:
Palladium acetate (2.8 mg, 0.013 mmol, 6% mol eq), rac-2,2′-bis(diphenylphosphino)1,1′-binaphthyl (16.2 mg, 0.026 mmol, 12% mol eq), and cesium carbonate (102.6 mg, 0.315 mmol, 1.5 eq) were added in anhydrous toluene under argon atmosphere. After stirring for 5 min, 3-(4-tert-butyl-2-trifluoromethanesulfonyloxyphenyl)acrylic acid ethyl ester (74.0 mg, 0.210 mmol, 1 eq) and N-Methylpiperazine (34.9 μl, 0.315 mmole, 1.5 eq) were added. The mixture was stirred for 24 hr at 80° C. The reaction mixture was purified according to step 1 of Example 22 to give yellow liquid (50.8 mg, 73.2%).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH3-]C#N.[Na+].[OH-].[K+]>CO.O>[CH2:2]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: Nc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CO
Solvent: O
Product: c1ccc(CN2CCCC(Nc3ccccc3)C2)cc1

Procedure:
To a solution of 1-benzyl-piperidin-3-one hydrochloride salt (2.02 g, 8.95 mmol), aniline (1.67 ml, 17.89 mmol) in MeOH (20 ml) at room temperature was added NaCNBH3 (1.8 g, 28.64 mmol) in several portions. The mixture was stirred over night. The mixture was taken up in 50 ml of water, the pH was increased to 12 with 2N KOH and extracted with CH2Cl2 (3×50 ml). Standard work-up of the organic solution provided 164 as a dried residue which was used in the next step without further purification. LRMS (calculated for C18H22N2) 266, found 266.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=O)[N:8]=2)=[CH:2]1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH2:30].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>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH:30][C:12]([C:9]1[N:8]=[C:7]([CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[O:11][N:10]=1)=[O:14]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)c1noc(Cc2ccsc2)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: O
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2ccsc2)n1
Yield: 29.1 %

Procedure:
This compound was prepared according to method F with ethyl 5-(thiophen-3-ylmethyl)-1,2,4-oxadiazole-3-carboxylate (0.103 g; 0.433 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.186 mL; 1.08 mmol), in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and preparative HPLC method 2 to yield 0.0487 g (29%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(thiophen-3-ylmethyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:16][C:15](N)=[N:14][N:13]=2)[CH2:8][CH2:7]1.[C:24]([Cu])#[N:25].O.C(Cl)Cl>CC#N>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[S:16][C:15]([C:24]#[N:25])=[N:14][N:13]=2)[CH2:10][CH2:11]1
Reactant: N#C[Cu]
Reactant: Nc1nnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: N#Cc1nnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Temperature: 55 °C

Procedure:
To a suspension of 5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2-amine (10.0 g, 29.0 mmol) in CH3CN (150 mL) was added CuCN (5.3 g, 59.2 mmol) and t-BuONO (90%) (8 mL, 60.0 mmol) at room temperature. The reaction mixture was heated at 50-60° C. for 2 h until TLC indicated disappearance of the starting material. The reaction mixture was poured into water and CH2Cl2 was added. The solid was removed by filtration and the filtrate was extracted with CH2Cl2, dried (Na2SO4) and filtered. Solvents were removed in vacuo to afford the crude product, which was purified by column chromatography on silica gel (eluting with 5:1 petroleum ether/EtOAc) to afford the title compound. 1H NMR (400 MHz, CDCl3): δ7.61 (d, 1H), 7.50 (t, 1H), 6.93-7.06 (m, 2H), 4.86 (br s, 1H), 3.77-3.83 (m, 4H), 2.01-2.20 (m, 4H). MS: m/z 355 (MH+).