Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])=[N:4][CH:3]=1.[CH:20]1([Mg]Br)[CH2:22][CH2:21]1>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([CH:20]2[CH2:22][CH2:21]2)([OH:8])[C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)c2ncc(Br)s2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](C(O)(c2ncc(Br)s2)C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl)carbonyl]cyclohexanecarboxylate (518 mg, 1.49 mmol) in anhydrous THF (16 ml) was treated dropwise over 20 min with cyclopropylmagnesium bromide (1.49 mmol, 0.5 M in tetrahydrofuran, 2.99 mL) at 0° C. under a nitrogen atmosphere. After stirring 1 h at room temperature, additional cyclopropylmagnesium bromide (2.23 mmol, 0.5 M in tetrahydrofuran, 4.48 mL) was added dropwise over 20 min at 0° C. and then the mixture was allowed to reach room temperature. After 4 h the mixture was diluted with saturated ammonium chloride and ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (0% to 20% EtOAc in hexanes) to afford racemic ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl)(cyclopropyl)hydroxymethyl]cyclohexanecarboxylate as a white solid. Two enantiomers were separated by chiral super critical fluid chromatography (Chiral Technology AS, 2.1×25 cm, 10 uM, 45/55 MeOH/CO2, Flow Rate: 70 mL/min, 14 min run time, WL: 220 nm) Elution was observed at 7.91 min and 10.78 min. Pooled fractions of each peak were concentrated under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9](I)[N:8]([CH3:13])[C:7]=1[CH3:14])=[O:5])[CH3:2].[CH3:15][O:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:17]=2[O:16][CH3:15])[N:8]([CH3:13])[C:7]=1[CH3:14])=[O:5])[CH3:2]
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)c1c(C)c(I)n(C)c1C
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: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)c(-c2cccc([N+](=O)[O-])c2OC)n(C)c1C
Temperature: 25 °C
Yield: 40.1 %

Procedure:
5-Iodo-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6e (2.88 g, 9.38 mmol) was dissolved in 25 mL of 1,4-dioxane followed by addition of 2-(2-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 6a (3.6 g, 10.3 mmol), tetrakis(triphenylphosphine)palladium (270 mg, 0.234 mmol), sodium carbonate (1.99 g, 18.77 mmol) and 10 mL of water. Upon completion of the addition, the reaction mixture was heated to reflux for 3 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was cooled to room temperature followed by addition of 30 mL of water and extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 5-(3-nitro-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6f (1.25 g, yield 40.4%) as a yellow oil.
Reaction SMILES: ClCl.[CH3:3][S:4][CH2:5][C:6]#[N:7].[NH2:8][C:9]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].C(N(CC)CC)C>C(Cl)Cl>[NH2:8][C:9]1[C:10]([C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:19][C:20]([O:23][CH3:24])=[CH:21][C:22]=1[CH:5]([S:4][CH3:3])[C:6]#[N:7]
Reactant: CSCC#N
Reactant: COc1ccc(N)c(C(=O)c2ccccc2)c1
Agent: ClCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)c2ccccc2)c(N)c(C(C#N)SC)c1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4.0 ml (0.088 mole) of chlorine in 200 ml of methylene chloride cooled to -70° C. is added dropwise a solution of 7.65 g (0.088 mole) of methylthioacetonitrile in 1 liter of methylene chloride while maintaining the temperature below -65° C. After several minutes a solution containing 0.2 mole of 2-amino-5-methoxybenzophenone in 100 ml of methylene chloride is added dropwise over a 30 min period. The mixture is stirred at -70° C. for about 1.5 hr and 18 g (0.18 mole) of triethylamine is added. The mixture is stirred for about an hour at -70° C. and then allowed to warm to ambient temperature. The mixture is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is recrystallized from a suitable solvent, e.g., 2-propanol, to give the title product.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[C:29]([NH2:32])[NH:30][N:31]=1>O1CCCC1>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[C:29]([NH:32][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[NH:30][N:31]=1
Reactant: COc1ccccc1-c1cc(N)[nH]n1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: COc1ccccc1-c1cc(NC=C2C(=O)Nc3ccccc32)[nH]n1

Procedure:
The named compound is prepared by substituting 5-(2-methoxy-phenyl)-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2551 gms. 5-(2-methoxy-phenyl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.0 mL) overnight.
Reaction SMILES: C(OCC)C.BrBr.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br:15][C:16]1[CH:17]=[C:18]2[C:28](=[CH:29][CH:30]=1)[O:27][C:21]1[CH:22]=[N:23][C:24]([Cl:26])=[CH:25][C:20]=1[C:19]2=[O:31]>[Zn].C1COCC1>[Br:15][C:16]1[CH:17]=[C:18]2[C:28](=[CH:29][CH:30]=1)[O:27][C:21]1[CH:22]=[N:23][C:24]([Cl:26])=[CH:25][C:20]=1[C:19]2([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[OH:31]
Reactant: CCOC(=O)CBr
Reactant: O=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Agent: BrBr
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 104.2 %

Procedure:
A 3-neck RBF equipped with an addition funnel and reflux condenser was charged with zinc dust (37.9 g, 580 mmol) and diethyl ether (300 ml). Bromine (1.544 ml, 29.0 mmol) was added drop wise to the stirring suspension at RT. After 5 minutes, ethyl 2-bromoacetate (32.3 ml, 290 mmol) was added drop wise via addition funnel over the time period of 1 hour. The reaction mixture was heated to reflux for one hour. 7-Bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one (30 g, 97 mmol) was added in one portion followed by THF (200 ml). After stirring at 40° C. for 10 minutes, the reaction mixture was cooled to RT and quenched with saturated aqueous ammonium chloride solution (250 mL). The reaction mixture was stirred for 1 hour before diluting with EtOAc and filtering through a pad of celite. The organic layer was separated, washed with brine and dried over MgSO4. The solution was concentrated under reduced pressure to afford ethyl 2-(7-bromo-3-chloro-5-hydroxy-5H-chromeno[2,3-c]pyridin-5-yl)acetate (40.3 g) which was used in the next step without further purification.
Reaction SMILES: C(O)CO.[CH2:5]([O:12][CH2:13][N:14]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH:30]3[CH2:32][CH2:31]3)[CH:20]=2)=[C:17]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[F:40])[C:16]([C:41]([O:43]CC)=O)=[C:15]1[CH:46]=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[NH2:49][NH2:50]>O>[CH2:5]([O:12][CH2:13][N:14]1[C:15]2[CH:46]=[N:49][NH:50][C:41](=[O:43])[C:16]=2[C:17]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[F:40])=[C:18]1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:27])[F:28])=[C:21]([O:29][CH:30]2[CH2:32][CH2:31]2)[CH:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1c(Cc2ccccc2F)c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCc2ccccc2)c1C=O
Solvent: O
Solvent: OCCO
Product: O=c1[nH]ncc2c1c(Cc1ccccc1F)c(-c1ccc(OC(F)F)c(OC3CC3)c1)n2COCc1ccccc1
Temperature: 130 °C
Reaction time: 8.5 h
Yield: 90.3 %

Procedure:
To 46 ml of ethylene glycol solution containing 5.01 g (8.44 mmol) of ethyl 1-benzyloxymethyl-5-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4-(2-fluorobenzyl)-2-formyl-1H-pyrrol-3-carboxylate obtained in the following Reference example 36-(f) was added 2.13 ml (42.5 mmol) of hydrazine monohydrate at 60° C., and then the mixture was stirred at 130° C. for 8.5 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:1→1:2 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 4.28 g of the title compound as a white solid. (Yield: 90%)
Reaction SMILES: [N:1]1[C:6]2[S:7][C:8]3[CH2:13][NH:12][CH2:11][CH2:10][C:9]=3[C:5]=2[C:4]([NH:14][C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)=[N:3][CH:2]=1.Cl.[CH3:23][N:24]([CH:31]([CH3:33])[CH3:32])[CH2:25]/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[CH3:23][N:24]([CH:31]([CH3:33])[CH3:32])[CH2:25]/[CH:26]=[CH:27]/[C:28]([N:12]1[CH2:11][CH2:10][C:9]2[C:5]3[C:4]([NH:14][C:15]4[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=4)=[N:3][CH:2]=[N:1][C:6]=3[S:7][C:8]=2[CH2:13]1)=[O:29]
Reactant: CC(C)N(C)C/C=C/C(=O)O
Reactant: Oc1cccc(Nc2ncnc3sc4c(c23)CCNC4)c1
Agent: Cl
Product: CC(C)N(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4cccc(O)c4)c23)C1

Procedure:
In analogy to Example 89, the title compound was prepared from 3-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol from Example 16A (100 mg, 0.25 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (68 mg, 0.35 mmol) to yield 35 mg (31%).
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]O)=[C:8]([O:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=2)[CH:7]=1>C(Cl)Cl>[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][Br:2])=[C:8]([O:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=2)[CH:7]=1
Reactant: BrP(Br)Br
Reactant: COc1cc(OC)cc(Oc2cc(Br)ccc2CO)c1
Solvent: ClCCl
Product: COc1cc(OC)cc(Oc2cc(Br)ccc2CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 224.1 %

Procedure:
In an argon atmosphere, 4.7 mL (F.W. 270.70, d=2.850, 49.5 mmol) of phosphorus tribromide was added to a solution of 46 g (F.W. 339.19, 135 mmol) of alcohol (23) in 100 mL of methylene chloride at 0° C. and stirred at room temperature for 30 minutes. To the reaction mixture was added ice water and the resulting solution was further stirred at room temperature for 30 minutes. The obtained solution was extracted with ethyl acetate and the extract was washed with water and then with a saturated sodium chloride aqueous solution. The resulting extract was dried with anhydrous magnesium sulfate and then, concentrated. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=1:5) to obtain 44.6 g (84%) of a bromide (24). (TLC; ethyl acetate:hexane=1:4)
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C@@H:12]2[CH2:16][NH:15][C@H:14]([C:17]3[NH:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[O:30][CH3:31])=[CH:24][CH:23]=4)=[CH:20][N:21]=3)[CH2:13]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].[CH3:33][C:34]([O:37][C:38]([NH:40][C:41]([C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][CH:44]=1)=[NH:42])=[O:39])([CH3:36])[CH3:35]>>[NH:42]=[C:41]([NH:40][C:38](=[O:39])[O:37][C:34]([CH3:35])([CH3:33])[CH3:36])[C:43]1[CH:44]=[CH:45][C:46]([C:47]([N:15]2[CH2:16][C@@H:12]([CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]3)[CH2:13][C@H:14]2[C:17]2[NH:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([O:30][CH3:31])=[O:32])=[CH:26][CH:27]=3)=[CH:20][N:21]=2)=[O:48])=[CH:50][CH:51]=1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(C(=O)O)cc1
Reactant: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3)[nH]2)cc1
Agent: Cl
Product: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)c3ccc(C(=N)NC(=O)OC(C)(C)C)cc3)[nH]2)cc1

Procedure:
The compound prepared in Example 66 was treated with the compound prepared in Example 18 following the procedure described in Example 8 to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].CCN=C=NCCCN(C)C.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.Cl.[F:71][C:72]([F:80])([F:79])[CH:73]1[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([N:76]3[CH2:77][CH2:78][CH:73]([C:72]([F:80])([F:79])[F:71])[CH2:74][CH2:75]3)=[O:40])=[CH:37][CH:38]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][Si:21]([CH:22]([CH3:23])[CH3:24])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:26])[CH3:27])[CH2:16][CH2:15]2)[C:10]1=[O:31]
Reactant: FC(F)(F)C1CCNCC1
Reactant: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Mix 3′,5′-Dichloro-4′-[(R)-2-oxo-trans-1-(4-triisopropylsilanyloxy-cyclohexyl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (Preparation 21) (0.94 g, 1.52 mmol), EDCI (0.358 g, 1.83 mmol), N-methylmorpholine (0.50 mL, 4.57 mmol), HOBT (0.511 g, 1.52 mmol) and 4-trifluoromethyl-piperidine hydrochloride (0.466 g, 3.05 mmol) in CH2Cl2 (15 mL). Stir for 12 hours at room temperature. Quench with 1N HCl and extract with ethyl acetate. Wash the extract with NaHCO3, brine. Dry over magnesium sulfate, filter, and concentrate. After flash column chromatography receive 0.586 g (51%) of the title compound: Mass spectrum (apci) m/z=753 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[C:22]2[N:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:16]([C:23]([OH:25])=O)=[CH:15][CH:14]=1.[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[N:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:30][CH2:29]1)[CH3:27]>>[CH2:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]2[N:40]=[CH:39][C:38]([NH:41][C:23]([C:16]3[C:17]4[N:18]=[CH:19][CH:20]=[N:21][C:22]=4[C:13]([C:3]4[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[F:12])=[CH:14][CH:15]=3)=[O:25])=[CH:37][CH:36]=2)[CH2:32][CH2:33]1)[CH3:27]
Reactant: CCN1CCN(Cc2ccc(N)cn2)CC1
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1F
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4c(F)c(OC)cc(OC)c4F)c4nccnc34)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 88.1), 6-(4-ethyl-piperazin-1-ylmethyl)-pyridin-3-ylamine (prepared as described in Example 39 but using N-ethyl-piperazine in Step 39.2), and stirring the reaction mixture for 3 h at rt. The crude product was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1). Title compound: ESI-MS: 549.1 [M+H]+; tR=3.22 min (System 1); TLC: Rf=0.13 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[O:14]=[C:4]1[CH:3]([CH2:2][O:1][C:29](=[O:30])[NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]1=2
Reactant: O=C1c2ccccc2SCCC1CO
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)OCC1CCSc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxymethyl-3,4-dihydro-2H-benzo[b]thiepin-5-one (359 mg, 1.726 mmol) in 22 ml of tetrahydrofuran were added, at 0° C., triethylamine (0.26 ml, 1.9 mmol) and phenyl isocyanate (410 μl, 3.8 mmol). The mixture was stirred at room temperature for 2 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 350 mg (62%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6]([NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:5]2[N:23]=[CH:24][N:25]=[C:4]2[N:3]=1.I[CH3:27].[H-].[Na+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:25]([CH3:27])[CH:24]=[N:23][N:5]2[C:6](=[N:17][CH2:18][C:19]([F:21])([F:20])[F:22])[C:7]=1[C:8]1[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=1[F:16]
Reactant: CI
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ncnn3c2NCC(F)(F)F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1cnn2c(=NCC(F)(F)F)c(-c3c(F)cc(F)cc3F)c(Cl)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
To a solution of 5-chloro-6-(2,4,6-trifluorophenyl)-N-(2,2,2-trifluoroethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (300 mg, 0.78 mmol) in 4 mL of dimethylsulfoxide at room temperature is added iodomethane (146 μL, 2.34 mmol) followed by sodium hydride (60% in mineral oil, 31 mg, 0.78 mmol). The mixture is then stirred at room temperature for 18 h, and diluted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride, dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with 20% ethyl acetate in hexanes. Concentration provides N-[5-chloro-3-methyl-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-ylidene]-2,2,2-trifluoroethanamine as a white solid (76 mg). MS: m/z 396.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][C:32]1([CH3:39])[C:36]([CH3:38])([CH3:37])[O:35][BH:34][O:33]1>C(#N)C>[CH3:31][C:32]1([CH3:39])[C:36]([CH3:38])([CH3:37])[O:35][B:34]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[CH:4][CH:3]=2)[O:33]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCc2ccc(Br)cc2)CC1
Reactant: CC1(C)OBOC1(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of tert-butyl 4-(3-(4-bromophenyl)propyl)piperazine-1-carboxylate (2.4 g, 6.26 mmol) in acetonitrile (12 ml) was added triethylamine (2.62 ml, 18.78 mmol) and Pd-118 (0.122 g, 0.19 mmol). Reaction mixture was stirred at RT under nitrogen for 10 min. 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.363 ml, 9.39 mmol) added and reaction mixture heated to 80° C. for 1 h. The reaction mixture was evaporated to dryness and redissolved in EtOAc and washed with water and saturated brine. The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography using Isco Companion, 100 g silica column, elution gradient 40 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford sub-title compound as a brown oil. Yield: 0.9 g
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([CH:21]3[CH2:23][CH2:22]3)([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]=[C:15]=3)O)[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)[OH:30]>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11]/[C:12](/[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:21]\[CH2:22][CH2:23][OH:30])[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(O)(C2=C=C=C(F)C=C2)C2CC2)C1
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2C/C(=C\CCO)c2ccc(F)cc2)C1
Temperature: 110 °C

Procedure:
2-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-cyclopropyl-1-(4-fluorocyclohexa-1,2,3,5-tetraenyl)ethanol (1 g, 25 mmol) was dissolved in 10 mL 25% sulfuric acid and heated at 110° C. for 4 h. The reaction mixture was cooled to RT, diluted with water and the resultant solid was filtered, washed with water, and diethylether. The solid was purified by reverse phase HPLC, and separated from the regioisomeric Compound No. 349. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.50 (m, 1H), 7.38 (d, 1H), 7.15 (m, 3H), 7.0 (m, 1H), 6.80 (m, 2H), 5.80 (m, 1H), 5.22 (m, 2H), 4.60 (m, 1H), 4.25 (m, 1H), 3.80 (m, 2H), 3.45 (m, 2H), 3.15 (m, 2H), 3.0 (s, 3H), 2.65 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1)=O>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[CH2:18][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(Cc2cccc([N+](=O)[O-])c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example I from 4-chloro-2-[(ethoxycarbonyl)amino]benzonitrile (Example 1, step 1) and 2-bromo-3′-nitroacetophenone.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:2]([F:1])([F:26])[O:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2ccc(OC(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(COC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a solution of tert-butyl 4-(4-(trifluoromethoxy)benzyloxy)piperidine-1-carboxylate (1.7 g, 4.53 mmol) in CH2Cl2 (15 mL, 3 mL/mmol) was added TFA (10 mL) and the mixture was stirred for 2 h at RT. The reaction mixture was concentrated under reduced pressure, taken up in chloroform, filtered and washed with diethyl ether to provide 4-(4-(trifluoromethoxy)benzyloxy) piperidine (1.2 g, 96%) as TFA salt. Observed mass (M+1): 276