Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2([OH:12])[CH2:11][CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[F:15][C:16]([F:21])([F:20])[C@@H:17]([OH:19])[CH3:18]>>[OH:12][C:8]1([C:7]2[C:2]([O:19][C@@H:17]([CH3:18])[C:16]([F:21])([F:20])[F:15])=[CH:3][C:4]([C:13]#[N:14])=[N:5][CH:6]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: C[C@H](O)C(F)(F)F
Reactant: N#Cc1cc(Cl)c(C2(O)CCC2)cn1
Product: C[C@H](Oc1cc(C#N)ncc1C1(O)CCC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 123c, using 4-chloro-5-(1-hydroxycyclobutyl)pyridine-2-carbonitrile (example 126b) and (S)-1,1,1-Trifluoro-propan-2-ol (CAN 3539-97-7) as starting materials and isolated (1.2 g, 92%); MS (ESI, m/z): 287.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([OH:8])[CH2:4][C:5]([CH3:7])=[CH2:6].[C:11](OC(=O)C)(=[O:13])[CH3:12].O>N1C=CC=CC=1>[Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([O:8][C:11](=[O:13])[CH3:12])[CH2:4][C:5]([CH3:7])=[CH2:6]
Reactant: C=C(C)CC(O)C(Cl)(Cl)Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: C=C(C)CC(OC(C)=O)C(Cl)(Cl)Cl
Yield: 91 %

Procedure:
A solution of 1,1,1-trichloro-2-hydroxy-4-methyl-4-pentene (65 g) in pyridine (100 ml) was heated with acetic anhydride (65 ml) at 100° C. for 3 hours. The reaction mixture was poured into water (600 ml) and the resulting solution extracted with ether (3×200 ml). The combined other phases were dried over MgSO4 and the ether was evaporated. Distillation and re-distillation yielded 71.4 g (91%) of 1,1,1-trichloro-2-acetoxy-4-methyl-4-pentene. B.p. 92°-96° C./11 mm Hg.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl.[N:29]([C@@H:32]1[CH2:37][CH2:36][C@@H:35]([NH2:38])[C@@H:34]([F:39])[CH2:33]1)=[N+:30]=[N-:31]>>[N:29]([C@H:32]1[CH2:37][CH2:36][C@H:35]([NH:38][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([CH:12]([F:14])[F:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[C@H:34]([F:39])[CH2:33]1)=[N+:30]=[N-:31]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Reactant: [N-]=[N+]=N[C@@H]1CC[C@@H](N)[C@@H](F)C1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N=[N+]=[N-])C[C@H]1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and (1R*,2S*,4R*)-4-azido-2-fluorocyclohexanamine hydrochloride (example C56) the title compound is obtained as pale yellow foam.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[C:10]([C:12]2[S:13][C:14]([O:18][CH3:19])=[C:15]([CH3:17])[N:16]=2)[CH:9]=[CH:8][C:6]=1[NH2:7])(=[O:4])=[O:3].[H-].[Na+].Cl[S:23]([C:26]1[S:30][C:29]2[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:28]=2[C:27]=1[CH3:36])(=[O:25])=[O:24].Cl>CC(N(C)C)=O.C1COCC1>[F:35][C:33]1[CH:32]=[CH:31][C:29]2[S:30][C:26]([S:23]([NH:7][C:6]3[CH:8]=[CH:9][C:10]([C:12]4[S:13][C:14]([O:18][CH3:19])=[C:15]([CH3:17])[N:16]=4)=[CH:11][C:5]=3[S:2]([CH3:1])(=[O:3])=[O:4])(=[O:24])=[O:25])=[C:27]([CH3:36])[C:28]=2[CH:34]=1
Reactant: COc1sc(-c2ccc(N)c(S(C)(=O)=O)c2)nc1C
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COc1sc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)nc1C
Temperature: -25 °C
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
Under an argon atmosphere, 41 mg of 2-methanesulfonyl-4-(5-methoxy-4-methylthiazol-2-yl)aniline was dissolved into a mixed solution of 3 mL of THF and 3 mL of dimethylacetamide. The solution was cooled to −25° C. and 15 mg of sodium hydride (oily, 60%) was added thereto, followed by 10 minutes of stirring at the same temperature. Further, 44 mg of 2-chlorosulfonyl-5-fluoro-3-methylbenzo[b]thiophene was added and the whole was stirred for 2 hours at the same temperature, followed by termination of the reaction with 1 mol/L hydrochloric acid. After the reaction mixture was warmed to room temperature, the mixture was extracted with ethyl acetate-toluene (2/1) and the organic layer was washed with water and saturated brine, successively. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to obtain 51 mg of the title compound as light yellow powder.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])[S:6][CH:7]=1.[O:14]1CCOCC1>O>[OH:14][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])[S:6][CH:7]=1
Reactant: CCOC(=O)Nc1nc(CCl)cs1
Reactant: C1COCCO1
Solvent: O
Product: CCOC(=O)Nc1nc(CO)cs1
Reaction time: 3.5 h
Yield: 98.2 %

Procedure:
A mixed solution of ethyl 4-(chloromethyl)-1,3-thiazol-2-ylcarbamate (500 mg) in 1,4-dioxane (5 ml) and water (10 ml) was refluxed with stirring for 3.5 hours. After cooling, it was concentrated under reduced pressure. The mixture was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10 g) using a mixed solvent of hexane and ethyl acetate (2:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give colorless syrup (450 mg, 98.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:20][C:21]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:22]=1[CH:23]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:23][C:22]4[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:21]=4[Cl:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: O=Cc1ccc(O)cc1Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ncnc(Nc3ccc(F)c(Cl)c3)c2C1=Cc1ccc(O)cc1Cl
Temperature: 25 °C

Procedure:
The mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (100 mg, 0.36 mmol), 2-chloro-4-hydroxy-benzaldehyde (84.5 mg, 0.54 mmol), and piperidine (3 drops), in ethanol (3 mL) was heated at 60° C. oil bath for 4 hours, and cooled to room temperature. The product was crystallized out, filtered, washed by ethanol, and dried under high vacuum to provide pure 4-(3-chloro-4-fluoro-phenylamino)-5-[-(2-chloro-4-hydroxy-phenyl)-methylidene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one. 1H NMR (400 MHz, DMSO-d6) d 11.52 (br s, 1H), 10.45 (br s, 1H), 8.42 (s, 1H), 8.35 (br s, 1H), 7.65 (s, 1H), 7.11 (t, 1H), 6.96 (m, 1H), 6.79 (m, 1H), 6.72 (d, 1H), 6.66 (m, 1H), 6.56 (dd, 1H). MS 418 [M++1].
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][N:43]([CH3:70])[C:44]([CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH2:65])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:55][CH:54]=1)=[O:45]>CN(C=O)C>[CH3:70][N:43]([CH3:42])[C:44]([CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH:65][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:57][CH:58]=1)=[O:45]
Reactant: O=C(O)c1c[nH]nn1
Reactant: CN(C)C(=O)COC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)COC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid dimethylcarbamoylmethyl ester (49 mg, 120 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (51 mg; purity 95%). MS m/z [M+H]+ calc'd for C26H31N5O5, 494.23. found 494.2.
Reaction SMILES: [CH3:1]O.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)[C:14]#[N:15].C[O-].[Na+].CI>O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)([CH3:1])[C:14]#[N:15]
Reactant: CO
Reactant: N#CC(Sc1nc2ccccc2s1)c1cccc(Oc2ccccc2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(C#N)(Sc1nc2ccccc2s1)c1cccc(Oc2ccccc2)c1
Reaction time: 2.5 h
Yield: 77 %

Procedure:
Methanol (5 ml) was added to 945 mg of alpha-(2-benzothiazolylthio)(m-phenoxyphenyl)acetonitrile, and the mixture was stirred under ice cooling in an argon atmosphere. Then, 1.0 ml of a 2.7 M methanol solution of sodium methoxide was added, and the mixture was stirred under ice cooling for 10 minutes. Methyl iodide (0.25 ml) was then added. The mixture was stirred under ice cooling for 30 minutes, and then at room temperature for 2.5 hours. Then, 30 ml of water was added, and the reaction mixture was extracted with 20 ml of methylene chloride three times. The extract was washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; benzene and methylene chloride) to afford 752 mg (yield 77%) of alpha-(2-benzothiazolylthio)-alpha-(m-phenoxyphenyl)propionitrile as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)[CH3:2].Br[C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:23][C:17]1[CH:16]=[CH:15][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)=[CH:19][C:18]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CCOc1cccc(B(O)O)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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Yield: 89.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0.8 g) was added to a mixture of 4.2 g of 3-ethoxyphenylboronic acid, 5.0 g of 5-bromo-2-fluoronitrobenzene and 22 ml of 2 M sodium carbonate solution in 50 ml of toluene and 50 ml of ethanol. The mixture was heated to reflux for 2 hours. The cooled mixture was concentrated, water was added and the mixture was extracted twice with ethyl acetate. The ethyl acetate layer was washed with water, brine, dried, and concentrated. The residue was chromatographed on silica gel (5% ethyl acetate in hexane) to give 5.3 g (90% yield) of crude 4-fluoro-3′-ethoxy-3-nitrobiphenyl as a yellow oil.
Reaction SMILES: C(OC([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH2:52][C:53]5[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=5)[CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl>[CH3:39][O:38][C:36](=[O:37])[C@@H:20]([NH:19][C:18]([C@@H:17]1[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH2:52][C:53]5[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=5)[CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9][NH:8]1)=[O:40])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=2[CH3:35])=[CH:24][CH:23]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)CO3
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)CO3
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (152 mg) was taken in 3 mL anhydrous DCM and cooled 0° C., HCl (0.75 mL, 4N in dioxane) was added and stirred at room temperature for 1 hour. All volatiles are evaporated and the residue was suspended in a 2N Na2CO3 solution and then extracted with EtOAc. The ethyl acetate layer was separated and washed with brine, and then dried (Na2SO4). The solvent was evaporated (105 mg). LCMS (m/z): 753.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7](=[O:9])[CH2:6][CH2:5][CH:4]([C:10]2[N:11]([CH3:18])[N:12]=[CH:13][C:14]=2[N+:15]([O-:17])=[O:16])[O:3]1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[CH3:1][CH:2]1[CH2:8][CH:7]([OH:9])[CH2:6][CH2:5][CH:4]([C:10]2[N:11]([CH3:18])[N:12]=[CH:13][C:14]=2[N+:15]([O-:17])=[O:16])[O:3]1
Reactant: CC1CC(=O)CCC(c2c([N+](=O)[O-])cnn2C)O1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CC(O)CCC(c2c([N+](=O)[O-])cnn2C)O1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
To a solution of 2-methyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-one (65 mg, 0.26 mmol) in THF (1 mL) under nitrogen cooled to −78° C. was added dropwise a solution of L-selectride (1 M in THF, 0.28 mL, 0.28 mmol). After 1 hr the mixture was quenched with MeOH (1 mL) and warmed to room temperature. EtOAc (10 mL) and brine (10 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (3×10 mL) and the combined organic layers were washed with brine (10 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 2-methyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-ol as a colourless solid (54 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 8.01 (2s, 1H), 5.63-5.59 and 5.56-5.50 (2m, 1H), 4.26-4.01 (m, 5H), 3.88-3.73 (m, 1H), 2.21-1.72 (m, 4H), 1.28-1.23 (m, 3H), 0.99-0.81 (m, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:26])=[C:6]([CH2:10][NH:11][C:12]2[N:13]=[C:14]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:15][C:16]=2[C:17]([NH2:19])=[O:18])[CH:7]=[CH:8][CH:9]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[S:28]>O1CCCC1>[Cl:3][C:4]1[C:5]([CH3:26])=[C:6]([CH2:10][N:11]2[C:12]3[N:13]=[C:14]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:15][C:16]=3[C:17](=[O:18])[NH:19][C:27]2=[S:28])[CH:7]=[CH:8][CH:9]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1Cn1c(=S)[nH]c(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 98 %

Procedure:
Sodium hydride (0.447 g, 17.71 mmol) was added portionwise to a suspension of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (0.812 g, 2.213 mmol) and 1,1′-thiocarbonyldiimidazole (1.183 g, 6.64 mmol) in Tetrahydrofuran (THF) (20 mL). The mixture was stirred at rt for 2.5 days, then quenched by the dropwise addition of saturated NH4Cl solution. The solvent was evaporated in vacuo and the residue was suspended in water. The pH was adjusted to about 6 by the addition of 1 N HCl. The yellowish orange solid was collected by filtration, washed with water, and dried in a vacuum oven at 65 C to provide 887 mg of the titled compound (98% yield). LC/MS: MS (ES+) m/e 409 (MH+)
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:35][CH3:36])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:18]>>[CH2:35]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][C:11]2=[O:16])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(-c4ccccc4)cc32)c1C
Yield: 38.6 %

Procedure:
5-Phenyl-1,3-dihydroindol-2-one (1.5 g, 7.16 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (2 g) to give 1.3 g (40%) of the title compound as a yellow-orange solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[N:20][C:21]2[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([CH:29]=2)[C:26]([OH:28])=[O:27])=[CH:15][CH:14]=1)=[N+:2]=[N-:3].[C:31](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]=[N:20][C:21]2[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([CH:29]=2)[C:26]([O:28][CH3:31])=[O:27])=[CH:17][CH:18]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCCCCCCOc1ccc(N=Nc2ccc(O)c(C(=O)O)c2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(N=Nc2ccc(OCCCCCCCCN=[N+]=[N-])cc2)ccc1O
Temperature: 25 °C
Yield: 50.5 %

Procedure:
To a stirred solution of 5-((4-(8-azidooctyloxy)phenyl)diazenyl)-2-hydroxybenzoic acid (400 mg, 0.97 mmol) in acetone (20 mL) was added powdered anhydrous potassium carbonate (270 mg, 1.94 mmol). Dimethyl sulfate (92 mg, 0.97 mmol) was then added dropwise at room temperature. The reaction mixture was heated at reflux for 20 min and then allowed to cool to ambient temperature. Volatiles were removed in vacuo, the residue taken up in EtOAc (40 mL), the solution washed with water (2×20 mL), brine, dried over Na2SO4, and filtered. Volatiles were removed in vacuo and the residue subjected to column chromatography on silica gel 60 (230-400 mesh) using EtOAc and hexanes (95:5) as the elutant to give 210 mg (0.49 mmol, 50%) of the product as a yellow solid, mp 58-60° C. 1H NMR (500 MHz, CDCl3) δ 1.39-1.51 (m, 8H), 1.64 (qt, 2H), 1.83 (qt, 2H), 3.28 (t, J=Hz, 2H), 4.02 (s, 3H), 4.05 (t, J=6.5 Hz, 2H), 7.88 (d, J=Hz, 2H), 8.07 (dd, J=Hz, 2.5 Hz, 1H), 8.42 (d, J=2.5 Hz, 1H), 11.06 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 25.9, 26.7, 28.8, 29.1, 29.2, 51.5, 52.5, 68.2, 112.4, 114.7, 118.3, 124.5, 126.0, 128.7, 145.5, 146.7, 161.5, 163.3, 170.3; HRMS (ESI) calculated for C22H28N5O4 (M+H)+426.2135, observed 426.2141.
Reaction SMILES: CC[O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][C:17]1[N:18]=[C:19]([CH3:22])[S:20][CH:21]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5].[OH-].[Na+]>C(O)C>[CH3:22][C:19]1[S:20][CH:21]=[C:17]([CH2:16][O:15][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]3)[N:18]=1
Reactant: CCOC(=O)c1cc2c(OCc3csc(C)n3)cccc2n1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(COc2cccc3[nH]c(C(=O)O)cc23)cs1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
4-(2-Methyl-thiazol-4-ylmethoxy)-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (169) (1.75 g, 4.2 mmol) is dissolved in 20 ml of ethanol. After addition of a 0.5M aqueous sodium hydroxide solution (33.6 ml, 16.8 mmol) the solution is heated to 60° C. and stirred at this temperature for 18 h. Then the reaction mixture is evaporated and the residue is dissolved in ethyl acetate. AT 0° C. conc HCl is added until a pH of 1 is reached. The organic phase is washed with water and brine. The organic layers are dried over sodium sulphate, filtrated. The product crystallized upon evaporation and could be filtrated off.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:17]=[C:16]([Cl:18])[C:15]([NH2:19])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>CC(O)=O>[C:1]([NH:19][C:15]1[C:16]([Cl:18])=[CH:17][C:9]([Cl:8])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(C(=O)O)c(Cl)cc1Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(C(=O)O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Acetic anhydride (27 mL) was added to 2,4-dichloro-5-aminobenzoic Acid 1-3 (8.0 g, 0.041 mol) in glacial AcOH (150 mL). The solution was stirred at room temperature for 30 min and concentrated to yield the desired acetamide 1-4 as a white solid (9.6 g, 96%). 1H NMR (400 MHz, CD3OD) δ2.19 (s, 3H), 7.62 (s, 1H), 8.32 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:10][N:11]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH:12]=1)=[O:5])[CH3:2].[CH3:29][C:30]1[O:34][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:32][C:31]=1[CH2:41][NH2:42].O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O.CN(C)C=O>[CH3:29][C:30]1[O:34][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:32][C:31]=1[CH2:41][NH:42][C:18]([C:17]1[CH:21]=[CH:22][C:14]([CH2:13][N:11]2[CH:12]=[C:8]([CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:10]2)=[CH:15][CH:16]=1)=[O:20]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(C(=O)O)cc2)nc1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(C(=O)NCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 82.8 %

Procedure:
A mixture of 4-[4-(2-ethoxycarbonylethyl)-3-phenyl-1H-pyrazol-1-ylmethyl]benzoic acid (500 mg), (5-methyl-2-phenyl-4-oxazolyl)methylamine (260 mg), 1-hydroxybenzotriazole monohydrate (210 mg), WSC (270 mg), and N,N-dimethylformamide (10 ml) was stirred at room temperature for 13 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution, 1 N hydrochloric acid, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The obtained yellow crystals were collected by filtration, and ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethylaminocarbonyl)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (600 mg, yield: 87%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 190–191° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[N:32]=[C:33]([C:36](O)=[O:37])[S:34][CH:35]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:33]4[S:34][CH:35]=[C:31]([CH3:30])[N:32]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: Cc1csc(C(=O)O)n1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2nc(C)cs2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 4-methylthiazole-2-carboxylic acid (21 mg, 0.15 mmol).