Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[N:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:14]2=[CH:13][C:12]=1[C:20](O)=[O:21].[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH2:31])[CH2:26][O:25]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH:31][C:20]([C:12]2[CH:13]=[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]3[C:11]=2[NH:10][C:3]2[CH:4]=[CH:5][C:6]([S:8][CH3:9])=[CH:7][C:2]=2[F:1])=[O:21])[CH2:26][O:25]1
Reactant: CSc1ccc(Nc2c(C(=O)O)cc3ccncn23)c(F)c1
Reactant: CC1(C)OC[C@H](CON)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc(Nc2c(C(=O)NOC[C@H]3COC(C)(C)O3)cc3ccncn23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
7-(2-Fluoro-4-methylsulfanyl-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (287 mg, 0.90 mmol), O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (133 mg, 0.90 mmol), HOBt (135 mg, 0.99 mmol), EDCI hydrochloride (191 mg, 0.99 mmol) and DIPEA (169 μL, 0.99 mmol) were dissolved in DMF (5 mL). The reaction was stirred at room temperature for 1 hour then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 30-100% ethylacetate in cyclohexane) to yield the title compound as a brown solid (246 mg, 61%). LCMS (Method B): RT=3.28 min, M+H+=447.
Reaction SMILES: [C:1]([OH:9])(=O)/[C:2](=[C:4](\[CH:6]=[O:7])/[Cl:5])/[Cl:3].[C:10]([CH2:12][C:13]([NH2:15])=[O:14])#[N:11].[OH-].[Na+].Cl>CO>[C:10]([CH:12]([CH:1]1[C:2]([Cl:3])=[C:4]([Cl:5])[C:6](=[O:7])[O:9]1)[C:13]([NH2:15])=[O:14])#[N:11]
Reactant: N#CCC(N)=O
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Temperature: 25 °C
Yield: 17.8 %

Procedure:
Mucochloric acid (15.1 g) and 2-cyanoacetamide (7.53 g) were dissolved in methanol (53.6 ml), and 2.5N aqueous sodium hydroxide solution (53.6 ml) was added dropwise with stirring under ice-cooling. The mixture was allowed to warm to room temperature, and further stirred at room temperature for 3 hr. The reaction mixture was poured into 1N hydrochloric acid containing ice water, methanol was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from ethanol-diisopropyl ether to give the title compound (3.74 g) as pale-brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][NH:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10]2)=[CH:5][CH:4]=1.O.[OH-].[Na+].[N+:22]([C:25]1[CH:35]=[CH:34][C:28]([CH2:29][O:30][C:31](Cl)=[O:32])=[CH:27][CH:26]=1)([O-:24])=[O:23]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:31]([O:30][CH2:29][C:28]3[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:35][CH:34]=3)=[O:32])[C@H:11]([C:14]([OH:16])=[O:15])[CH2:10]2)=[CH:17][CH:18]=1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(=O)O)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 77.5 %

Procedure:
A suspension of 1.87 g of (2S,4S)-4-(4-methoxybenzylthio)-2-pyrrolidinecarboxylic acid [prepared as described in step (i) above] in 80 ml of a 1:1 by volume mixture of tetrahydrofuran and water was transformed to a homogeneous solution by adding 7 ml of a 1N aqueous solution of sodium hydroxide. The solution was ice-cooled and stirred, and, little by little, a solution of 1510 mg of 4-nitrobenzyloxycarbonyl chloride in 10 ml of tetrahydrofuran and 7 ml of a 1N aqueous solution of sodium hydroxide were simultaneously added dropwise. The resulting mixture was stirred at the same temperature for 10 minutes. At the end of this time, the reaction mixture was freed from tetrahydrofuran by distillation under reduced pressure, and its pH was adjusted to a value of between 2 and 3 by the addition of 1N aqueous hydrochloric acid. The crystals which precipitated were collected by filtration, washed well with water and subjected to air-drying. The crystals were further washed with a small amount of diethyl ether and dried, to give 2.42 g of the title compound, melting at 96°-98° C.
Reaction SMILES: [CH2:1]([N:4]1[C:9]([CH3:10])=[CH:8][C:7]([OH:11])=[CH:6][C:5]1=[O:12])[CH:2]=[CH2:3].C1C(=O)N(Br)C(=O)C1.[Cl:21]C(Cl)C(O)=O>CC#N>[CH2:1]([N:4]1[C:9]([CH3:10])=[CH:8][C:7]([OH:11])=[C:6]([Cl:21])[C:5]1=[O:12])[CH:2]=[CH2:3]
Reactant: O=C(O)C(Cl)Cl
Reactant: C=CCn1c(C)cc(O)cc1=O
Agent: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: C=CCn1c(C)cc(O)c(Cl)c1=O
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a stirred solution of 1-allyl-4-hydroxy-6-methylpyridin-2(1H)-one (500 mg, 3.0 mmol) in CH3CN(10 ml), at rt, was added sequentially n-bromosuccinimide (440 mg, 3.3 mmol) and dichloroacetic acid (546 μl, 6.62 mmol). The resulting mixture was stirred for 2 h. The heterogeneous mixture was filtered and the solid was washed with additional CH3CN to give 350 mg (59%) of the desired product as a tan solid. 1H-NMR (DMSOd6/300 MHz) δ 11.16 (s, 1H), 5.98-5.86 (m, 2H), 5.12 (dd, J=10.5, 1.5 Hz, 1H), 4.89 (dd, J=17.1, 1.5 Hz, 1H), 4.63-4.61 (m, 2H), 2.29 (s, 3H). ES-HRMS m/z 200.050 (M+H calcd for C9H11ClNO2=200.0470)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16](COCC[Si](C)(C)C)[CH:17]=[CH:18][C:11]=12)[NH2:5].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5]
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cc3ccc(N)cc3F)ccnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Cc2ccnc3[nH]ccc23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
477 mg (1.00 mmol) of 3-fluoro-4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl]aniline are dissolved in 4 ml of dichloromethane. 4.0 ml of trifluoroacetic acid are added, and the mixture is stirred at RT for 2 hours. The solution is concentrated to dryness. The residue is taken up in 15 ml of THF, and 15 ml of an aqueous 1 M lithium hydroxide solution are added. The solution is stirred at RT for 20 hours and then concentrated, and water is added. The mixture is extracted with ethyl acetate. The extract is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:21]([NH:22][CH3:23])[CH2:20][CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.[CH2:26]([N:28](CC)[CH2:29]C)C.Cl[C:34](=[O:39])[C:35](OC)=[O:36]>ClCCl.O.C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:21]([N:22]([CH3:23])[C:35](=[O:36])[C:34]([N:28]([CH3:29])[CH3:26])=[O:39])[CH2:20][CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:24][CH:25]=1
Reactant: CNC1CCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Reactant: COC(=O)C(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CN(C)C(=O)C(=O)N(C)C1CCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of crude N-(4-fluorobenzyl)-3-hydroxy-9-(methylamino)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide (synthesized as described in Example 3, Step 3) in dichloromethane were added 6 eq. of triethylamine and 6 eq. of methyl chlorooxoacetate. The mixture was stirred at room temperature for 2 h, the solvent was removed under reduced pressure and the residue was dissolved in a solution of dimethylamine (2 M) in tetrahydrofuran. The mixture was stirred at 57° C. overnight. After cooling to room temperature, the solvent was removed under reduced pressure and the product was isolated by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluents (column: C18). The pooled product fractions were lyophilized to afford the title compound as a fluffy, slightly pink material. The product was a mixture of rotamers by NMR.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].Br[C:38]1[CH:39]=[N:40][C:41]([C:44]([NH:46][CH:47]2[CH2:49][CH2:48]2)=[O:45])=[N:42][CH:43]=1>>[C:3]([C:2]([CH3:36])([CH3:1])[CH2:5][C@@:6]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:16]=[CH:17][C:18]([C:38]3[CH:39]=[N:40][C:41]([C:44]([NH:46][CH:47]4[CH2:48][CH2:49]4)=[O:45])=[N:42][CH:43]=3)=[CH:19][CH:20]=2)[CH3:14])[CH2:8][CH2:7]1)#[N:4]
Reactant: O=C(NC1CC1)c1ncc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cnc(C(=O)NC3CC3)nc2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile and 5-bromo-N-cyclopropylpyrimidine-2-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.237 min, m/z=524.3; 1H NMR (CDCl3) 0.62 (m, 2H), 0.83 (m, 2H), 1.32 (s, 3H), 1.44 (s, 3H), 1.49 (d, 3H), 2.08 (m, 2H), 2.24 (m, 1H), 2.42 (m, 2H), 2.90 (m, 2H), 5.61 (m, 1H), 6.93 (m, 2H), 7.20-7.36 (m, 7H), 8.00 (s, 1H), 8.88 (s, 2H).
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][N:4]1[CH:9]([NH:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[CH:7][C:6]([O:21][C:22]2[CH:23]=[CH:24][C:25]([CH3:38])=[C:26]([NH:28][C:29]([C:31]3[N:35]([CH3:36])[N:34]=[C:33]([CH3:37])[CH:32]=3)=[O:30])[CH:27]=2)=[CH:5]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]2[CH:8]=[CH:7][C:6]([O:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:38])=[C:26]([NH:28][C:29]([C:31]4[N:35]([CH3:36])[N:34]=[C:33]([CH3:37])[CH:32]=4)=[O:30])[CH:27]=3)=[CH:5][N:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC2C=CC(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)=CN2CC(N)=O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4c3)ccc2C)n(C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.4 %

Procedure:
A mixture of N-{5-[(1-(2-amino-2-oxoethyl)-6-{[(4-methylphenyl)sulfonyl]amino}-1,6-dihydropyridin-3-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (2.34 g, 4.27 mmol), trifluoroacetic anhydride (15 mL) and dichloromethane (20 mL) was stirred at room temperature for 5 hr. The reaction solution was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution (20 mL) and ethanol (20 mL) were added to the residue and the mixture was stirred at room temperature for 1 hr. 8N Aqueous sodium hydroxide solution (4 mL) was further added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give N-{5-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (1.10 g, 68%) as a white solid. To a solution of N-{5-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (1.10 g, 2.92 mmol) thus-obtained and triethylamine (1.21 mL, 8.76 mmol) in tetrahydrofuran (15 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (345 μL, 3.80 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=70/30→40/100) and recrystallized from ethyl acetate-hexane to give the title compound (863 mg, 60%) as a white solid.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([P:8](OCC)(=[O:12])[O:9][CH2:10][CH3:11])[CH2:6][CH3:7]>C(S)CC>[CH2:10]([O:9][P:8]([CH2:5][CH2:6][CH3:7])([CH2:3][CH2:2][C:1]#[N:4])=[O:12])[CH3:11]
Reactant: CCCP(=O)(OCC)OCC
Reactant: C=CC#N
Agent: CCCS
Product: CCCP(=O)(CCC#N)OCC
Yield: 94.4 %

Procedure:
53 g of acrylonitrile are added dropwise under nitrogen at a reaction temperature of 70° C. to a mixture of 160 g of diethyl propanephosphonate in 100 g of n-propylmercaptan in the course of 2 hours. After a further 3 hours the solvent (low-boiling solvent such as C3H7SC2H5 and excess C3H7SH) is removed by vacuum distillation; the crude product is obtained in a yield of 173 g with a 95.4% purity, which corresponds to a theoretical yield of 94.4%. The boiling point of the product is 117°-118° C. at 0.027 mbar.
Reaction SMILES: [C:1]([O:4][CH:5]([CH:9]([S:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[NH:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33](C2C=CC=CC=2)[CH2:32][CH2:31]1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:6](O)=[O:7])(=[O:3])[CH3:2].[C:42]([O-:47])(=[O:46])[C:43]([O-:45])=[O:44]>>[C:42]([O-:47])(=[O:46])[C:43]([O-:45])=[O:44].[C:1]([O:4][C@H:5]1[C:6](=[O:7])[N:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][NH:33][CH:34]([C:43]3[CH:42]=[CH:10][CH:9]=[CH:5][CH:6]=3)[CH2:35]2)[C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[S:18][C@H:9]1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(Sc2cc(Cl)ccc2NCCCN2CCN(c3ccccc3)CC2)C(OC(C)=O)C(=O)O)cc1
Agent: O=C([O-])C(=O)[O-]
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCCN3CCNC(c4ccccc4)C3)C(=O)[C@@H]2OC(C)=O)cc1
Yield: 48.4 %

Procedure:
2-Acetoxy-3-[5-chloro -2-[3-(4-phenylpiperazin-1-yl) propyl]aminophenylthio]-3-(4-methoxyphenyl)propionic acid (VT b+VE b, threo/erythro=8.61/1) (2.006 g, 3.353 mmol) is subjected to a ring closure reaction in a similar manner to that described in Example 13 to obtain crude product (cis-VIb +trans-VIb) (1.941 g). This crude product is converted to its oxalate, which is recrystallized to obtain oxalate of (+)-cis-3-acetoxy-8-chloro-2,3-dihydro-2-(4-methoxyphenyl)-5-[3-phenylpiperazin-1-yl]propyl -1,5-benzothiazepine- 4(5H)-one (cis-VIb) (1. 298 g, yield=48.4%) as colorless prism-shaped crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([N:12]2[C@@H:19]3[C@@H:14]([CH2:15][CH2:16][NH:17][CH2:18]3)[CH2:13]2)[CH:3]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[CH3:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[C:39]([N:46]2[CH:50]=[CH:49][N:48]=[N:47]2)[N:38]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>>[CH3:36][C:37]1[N:38]=[C:39]([N:46]2[CH:50]=[CH:49][N:48]=[N:47]2)[C:40]([C:41]([N:17]2[CH2:16][CH2:15][C@@H:14]3[C@@H:19]([N:12]([C:4]4[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[N:5]=4)[CH2:13]3)[CH2:18]2)=[O:42])=[CH:44][CH:45]=1
Reactant: Cc1cc(N2C[C@@H]3CCNC[C@@H]32)nc(C(F)(F)F)n1
Reactant: Cc1ccc(C(=O)O)c(-n2ccnn2)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4ccc(C)nc4-n4ccnn4)C[C@@H]32)nc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-[8-(6-methyl-2-trifluoromethyl-pyrimidin-4-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 9) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid (Intermediate 51) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. For C21H21F3N8O, 458.45; m/z found 459.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][C@H:8]([NH2:16])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O=C1CCC(=O)N1[O:25][C:26]([C@@H:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:34](=[O:50])[CH2:35][CH2:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)[CH2:29]1)=O.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O.ClCCl>[C:46]([O:45][C:43]([N:40]1[CH2:39][CH2:38][CH:37]([CH2:36][CH2:35][C:34]([N:30]2[CH2:31][CH2:32][CH2:33][C@@H:28]([C:26](=[O:25])[NH:16][C@H:8]([C:9]3[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=3)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:17])[CH2:29]2)=[O:50])[CH2:42][CH2:41]1)=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)C[C@H](N)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)ON3C(=O)CCC3=O)C2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 101.9 %

Procedure:
214.0 mg (0.90 mmol) (S)-3-amino-3-(4-hydroxy-phenyl)-propionic acid tert-butyl ester were dissolved in 3.5 ml N,N-dimethylformamide and cooled to 0° C. To this solution was added a solution of 466.4 mg (1.00 mmol) tert-butyl 4-{3-[(3R)-3-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 5c) and 0.38 ml (2.71 mmol) triethylamine in 3.5 ml dichloromethane. The mixture was kept at 6° C. for 20 hours. Saturated ammonium chloride solution was added and the mixture extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuum to give 820 mg. Chromatography over 5 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 539 mg (102%) 4-(3-{(R)-3-[(S)-2-tert-butoxycarbonyl-1-(4-hydroxy-phenyl)-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:30]([O:32][C:33](=[O:50])[CH2:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1)[CH3:31]>>[CH2:30]([O:32][C:33](=[O:50])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([C:16]3[N:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)[CH:20]=3)[OH:15])=[CH:6][CH:7]=2)=[CH:37][CH:36]=1)[CH3:31]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3C(O)c3cn(Cc4ccc(Cl)c(Cl)c4)nn3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3,4-dichloro-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[C:22]([N:24]3[CH:28]=[C:27]([CH2:29][CH2:30][OH:31])[N:26]=[N:25]3)[CH:21]=[CH:20][C:19]=2[CH3:32])=[O:17])=[C:12]([CH3:33])[CH:11]=1.BrC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.NC1C=CC=CC=1>>[OH:31][CH2:30][CH2:29][C:27]1[N:26]=[N:25][N:24]([C:22]2[CH:21]=[CH:20][C:19]([CH3:32])=[C:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:3]4[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:11][C:12]=3[CH3:33])=[O:17])[CH:23]=2)[CH:28]=1
Reactant: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Agent: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Solvent: Nc1ccccc1
Product: Cc1cc(Nc2ccccc2)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and aniline (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM/petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the eluent to afford the title compound as yellow solid. 13C NMR (CDCl3) δ 197.0, 147.9, 146.3, 143.4, 142.5, 140.4, 137.0, 135.5, 134.6, 132.2, 129.5, 127.6, 123.5, 121.4, 121.0, 119.9, 118.1, 111.4, 61.6, 28.7, 22.3, 19.5
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].O>CS(C)=O>[N+:14]([C:9]1[CH:8]=[C:13]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:12]=[CH:11][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Temperature: 100 °C
Yield: 64.7 %

Procedure:
28.4 g (0.33 mol, 5.5 eq) of piperazine is dissolved in 50 ml of DMSO. 6.4 ml (60 mmol) of 2-fluoronitrobenzene is added. The mixture is heated at 100° C. for 60 hours. After cooling, the reaction mixture is transferred into 530 ml of water. The precipitate formed is filtered and the filtrate extracted with Et2O. After drying on MgSO4 and concentration under vacuum, the crude product is purified by column chromatography (eluent CH2Cl2/MeOH 9:1) to produce 8.04 g of the expected compound in the form of an orange oil which crystallizes at room temperature (yield: 65%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][N:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:23]=[CH:22]4)[C:15]2=[O:35])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CC(O)=O.[Pd]>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:23]=[CH:22]4)[C:15]2=[O:35])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=c1n(-c2ccc(Oc3ccccc3)cc2)ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1N(c2ccc(Oc3ccccc3)cc2)CCN1c1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1-(4-phenoxyphenyl)-3-[1-(2-pyrrolidin-1-ylethyl)-1H-indazol-5-yl]-1,3-dihydro-2H-imidazol-2-one (Example 118) (0.100 g, 0.215 mmol) was dissolved in 20 mL of AcOH and 100 mg of Pd/C (10% mol/mol) was added. The mixture was subjected to an atmosphere of hydrogen gas at a pressure of 60 psi in a Parr shaker apparatus, and shaken at room temperature for 6 hours. The mixture was filtered through celite, and the solvents removed under reduced pressure. The residue was purified by RP-HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.52–1.77 (m, 4 H) 2.34–2.50 (m, 4 H) 2.87 (t, J=6.61 Hz, 2 H) 3.88–4.13 (m, 4 H) 4.50 (t, J=6.61 Hz, 2 H) 6.93–7.02 (m, J=7.80 Hz, 2 H) 7.03–7.15 (m, 3 H) 7.33–7.45 (m, J=8.65, 7.29 Hz, 2 H) 7.61–7.72 (m, 3 H) 7.72–7.78 (m, J=2.03 Hz, 1 H) 7.79–7.89 (m, 1 H) 8.02 (s, 1 H); MS (ESI) m/z 468 [M+H]+.
Reaction SMILES: C(#[N:3])C.Cl[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10]([N:12]([CH2:15]C)[CH2:13]C)[CH3:11]>>[CH3:13][N:12]1[CH:10]=[CH:11][N:3]=[C:15]1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC#N
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Product: CCOC(=O)c1nccn1C
Temperature: -20 °C
Yield: 82 %

Procedure:
N-methylnimdazole (320 g, 3.9 mol) was combined with 2 L acetonitrile and 1 L triethylamine in a 12 L flask equipped with a mechanical stirrer and the solution cooled to -20° C. Ethyl chloroformate (1000 g, 9.2 mol) was added with stirring, keeping the temperature between -20° C. and -25° C. The reaction was allowed to slowly warm to room temperature and stir for 36 h. Precipitated triethylamine hydrochloride was removed by filtration and the solution concentrated in vacuo at 65° C. The resulting oil was purified by distillation under reduced pressure (2 torr, 102° C.) to provide a white solid (360 g, 82% yield).