Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13](O)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:23].F[P-](F)(F)(F)(F)F.CNC.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:13](=[O:14])[N:22]([CH3:23])[CH3:21])[CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (100 mg, 0.3 mmol), HATU (188 mg, 0.5 mmol), dimethylamine (0.2 mL, 2M in THF) and DIPEA (0.23 mL, 1.3 mmol) in DMF (2 mL) was stirred for 16 h at ambient temperature. The crude product was purified without aqueous workup by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 ml/min) to give the title compound. MS (LC-MS): 275.0 [M−55]+; tR (HPLC conditions c): 4.68 min.
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].O1CCCC1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]#[N:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(Br)C=C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]([CH2:3][CH:1]=[CH2:2])([C:27]#[N:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: CC(C)[N-]C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2M lithium diisopropylamide-tetrahydrofuran solution (9.96 ml) in tetrahydrofuran (20 ml) was dropwise added a solution of 4-cyanopiperidine-1-carboxylic acid tert-butyl ester (3.5 g) in tetrahydrofuran (15 ml) at −78° C. and under argon atmosphere, and the mixture was stirred at room temperature for 30 min. Then, allyl bromide (2.15 ml) was added at −78° C., and the mixture was stirred at the same temperature for 30 min and at room temperature for 1 hour. After completion of the reaction, 10% aqueous citric acid was added and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) and dried under reduced pressure to give the title compound (3.5 g).
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.[C:37]([O:41][C:42]([N:44]1[CH2:48][CH2:47][CH2:46][C@H:45]1[C:49](O)=[O:50])=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][C:49]([C@@H:45]5[CH2:46][CH2:47][CH2:48][N:44]5[C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])=[O:50])[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Product: CC(OC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Yield: 78 %

Procedure:
In analogy to Example 5, 330 mg (0.65 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using (S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and, after workup and purification, 356 mg (78%) of the title compounds were isolated as a colourless foam.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:26])[C:17]2[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([C:24]#[N:25])[CH:18]=2)[CH:6]=[CH:7][C:8]=1[C@@H:9]1[O:14][CH2:13][CH2:12][NH:11][CH2:10]1.C(OC(N1CCO[C@@H](C2C=CC(N)=C([F:47])C=2)C1)=O)(C)(C)C>>[ClH:2].[C:24]([C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([CH3:23])[N:20]=1)[C:16]([NH:15][C:5]1[CH:6]=[CH:7][C:8]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:3][C:4]=1[F:47])=[O:26])#[N:25]
Reactant: Cc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)c(Cl)c2)cc(C#N)n1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(F)c2)C1
Agent: Cl
Product: Cc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)cc2F)cc(C#N)n1

Procedure:
In analogy to example 83, step a) using 2-Cyano-6-methyl-isonicotinic acid (described in example 112) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (preparation described in example 1-h) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[CH:38]=[CH:37][C:28]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1>>[C:29]([C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]2)[CH2:10][CH2:11]3)=[O:3])=[CH:38][CH:37]=1)(=[O:30])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(C(=O)c4ccccc4)cc3)(CC1)CC2
Yield: 14.8 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-aminobenzophenone (67.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-benzoylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (11.5 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][CH2:14][CH3:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N:16]([O-])=O.[Na+].O.N.C(OCC)(=O)C>C(O)(=O)C>[CH2:14]([N:13]1[C:12]2[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=2[N:1]=[N:16]1)[CH3:15]
Reactant: O=N[O-]
Reactant: CCNc1ccc(C(=O)OCC)cc1N
Agent: N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)nnn2CC
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
Ethyl 3-amino-4-ethylaminobenzoate (1.80 g, 9.27 mmol) prepared in the same manner as in the Step 1-1-3 was dissolved in acetic acid (5 ml), and under an ice cooling sodium nitrite (1.28 g, 18.5 mmol) was added to the solution little by little. The mixture was stirred for 10 minutes under a water cooling. The mixture was cooled by ice again and neutralized with a 25% ammonia water. Thereafter, ethyl acetate was added to the mixture, and the resulting mixture was washed with a saturated saline solution and water in order. The washed mixture was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1 to 1:1) to give the title compound (1.40 g, 69%) as a brown powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[Br:11][C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[C:15]([OH:22])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:11][C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[C:15]([O:22][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(CBr)cc1
Reactant: COC(=O)c1nc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1nc(Br)ccc1OCc1ccc(OC)cc1
Temperature: 25 °C

Procedure:
4-Methoxybenzyl bromide (0.095 g, 0.47 mmol) was added dropwise to a suspension of methyl 6-bromo-3-hydroxypicolinate (26B) (0.100 g, 0.43 mmol) and K2CO3 (0.089 g, 0.65 mmol) in anhydrous acetone (2.5 mL). The reaction mixture was heated at reflux for 3.5 hours, cooled to rt, and concentrated under reduced pressure. Water was added and the mixture extracted with DCM. The organic phases were washed with 1 M NaOH, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc 84:16 to 72:28, to provide the desired product methyl 6-bromo-3-(4-methoxybenzyloxy)picolinate (40A).
Reaction SMILES: [O:1]=[C:2]1[C@@H:6](OS(C)(=O)=O)[CH2:5][CH2:4][NH:3]1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[C:18]1([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH2:17]2.CCN(C(C)C)C(C)C>C(#N)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[C:18]1([CH2:23][CH2:22][N:21]([CH:6]3[CH2:5][CH2:4][NH:3][C:2]3=[O:1])[CH2:20][CH2:19]1)[CH2:17]2
Reactant: COc1ccc2c(c1)CC1(CCNCC1)C2=O
Reactant: CS(=O)(=O)O[C@H]1CCNC1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CC1(CCN(C3CCNC3=O)CC1)C2=O
Temperature: 85 °C
Yield: 77.3 %

Procedure:
To a 250 mL round bottom flask was added methanesulfonic acid (S)-2-oxo-pyrrolidin-3-yl ester (2) (4.76 mmol, 852 mg) and 5-methoxyspiro[indene-2,4′-piperidin]-1(3H)-one (3) (4.32 mmol, 1.00 g) in DIEA (17.29 mmol, 3.02 mL) and acetonitrile (20 mL). The solution was then heated to 85° C. for 90 min. The reaction was concentrated in vacuo and flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate afforded the title compound (1.05 g, 77% yield). Calculated MS=306.2. found MS (ESI) m/e 307.3 (M+H+); HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.253 min.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:5]([Cl:31])=[CH:6][C:7]2[C:8]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19][C:9]=3[N:10]([CH2:13][C:14]([O:16]CC)=[O:15])[C:11]=2[CH:12]=1.Cl>O.C1COCC1>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][C:8]2[C:7]3[CH:6]=[C:5]([Cl:31])[C:4]([Cl:3])=[CH:12][C:11]=3[N:10]([CH2:13][C:14]([OH:16])=[O:15])[C:9]=2[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)c(Cl)cc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3cc(Cl)c(Cl)cc23)CC1
Temperature: 60 °C
Yield: 109.8 %

Procedure:
A solution of KOH (0.17 g, 3.0 mmol) in H2O (10 mL) was added to a solution of tert-butyl 8,9-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.00 g, 2.27 mmol) in THF (15 mL). The mixture was heated at 60° C. for 2 h. The reaction was then cooled to rt, acidified with 10% aqueous HCl, and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated to give crude acid (1.03 g, 110%): 1H NMR (300 MHz, CDCl3) δ 7.50 (s, 1H), 7.26 (s, 1H), 4.73 (s, 2H), 3.74 (m, 2H), 3.67 (m, 2H), 2.89 (m, 4H), 1.47 (s, 9H); MS(ESI+) m/z 410.9.
Reaction SMILES: C(OCC)(=O)C.CCCCCC.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:27])=[CH:16][CH:15]=1.[Br:35]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:35][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])=[O:27])=[CH:18][CH:19]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)OCC[Si](C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOC(=O)c1ccccc1-c1ccc(CBr)cc1

Procedure:
The starting material can be obtained, for example, as follows: 14.2 g of 4-methyl-2'-carboxybiphenyl (EP 253,310) are dissolved in 60 ml of acetonitrile and 10.7 ml of pyridine and 11.4 ml of trimethylsilylethanol are added. The mixture is treated at 0° with 15.1 g of dicyclohexylcarbodiimide and stirred at this temperature for 3 hours. After this, the reaction mixture is evaporated in a high vacuum, the residue is treated with ether, and dicyclohexylurea is filtered off. After flash chromatography (ethyl acetate/hexane 95:5), 4-methyl-2'-(trimethylsilylethoxycarbonyl)biphenyl is obtained as a slightly yellowish oil. (TLC: ethyl acetate/hexane 95:5) Rf : 0.42. 312 mg of 4-methyl-2'-(trimethylsilylethoxycarbonyl)biphenyl, 178 mg of N-bromosuccinimide, 5 mg of azoisobutyronitrile and 15 ml of carbon tetrachloride are heated to reflux for one hour. After cooling, the mixture is evaporated. Flash chromatography (ethyl acetate/hexane 95:5) yields 4-bromomethyl-2'-(trimethylsilylethoxycarbonyl)biphenyl as a slightly yellowish oil. 1H-NMR (CFCl3): 0 ppm (s, 9H), 0.7 ppm (t, 2H), 4.5 ppm (s, 2H), 7.1-8 ppm aromatics.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([OH:13])=[CH:11][C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:9]1.C(O)(=O)C.[Cl:23][CH2:24][C:25](OCC)(OCC)[O:26]CC>C(#N)C>[Cl:23][CH2:24][C:25]([C:11]1[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:12]=1[OH:13])=[O:26]
Reactant: COC(=O)Cc1cc(O)n(-c2ccccc2Cl)n1
Reactant: CCOC(CCl)(OCC)OCC
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)Cc1nn(-c2ccccc2Cl)c(O)c1C(=O)CCl

Procedure:
The mixture of the above obtained methyl [1-(2-chlorophenyl)-5-hydroxy-1H-pyrazol-3-yl]acetate (Compound of Formula (IV), 0.60 g), was suspended in acetonitrile (5 mL) and glacial acetic acid (14 mg, 0.1 eq.) and 2-chloro-1,1,1-triethoxyethane (1.5 g) under nitrogen, was heated at 70° C. for 45-60 minutes. The resulting red solution was concentrated in vacuo to afford a red syrup that was washed with cyclohexane and then dried in vacuo. Due to its relative instability, no further purification of methyl [4-(chloroacetyl)-1-(2-chlorophenyl)-5-hydroxy-1H-pyrazol-3-yl]acetate was conducted (0.77 g, quantitative yield). MS (ESL): 344.3; MS (ESI−): 342.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[CH:19]=1)[C:5]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH3:9])=[O:6].[CH3:26][N:27](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:26]([C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[CH:19]=1)[C:5]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH3:9])=[O:6])#[N:27]
Reactant: C[C@@H](NC(=O)c1cc(Br)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@@H](NC(=O)c1cc(C#N)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1

Procedure:
To a solution of 3-bromo-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (Intermediate X) (0.033 g, 0.077 mmol) in 0.80 mL degassed DMF (degassed by bubbling a stream of argon through solvent for 5 min) was added Zn(CN)2 (0.011 g, 0.092 mmol) and Pd(PPh3)4 (0.009 g, 0.008 mmol). The reaction vessel was purged thoroughly with argon, then sealed and microwaved at 180° C. for 30 min. The reaction was diluted with EtOAc, and the organics were washed with 3M aqueous LiCl. The aqueous washed with fresh EtOAc (2×), the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (5->75% EtOAc/hexanes) to afford 3-cyano-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide as a white foam. 1H NMR (CDCl3, 400 MHz) δ 8.04 (t, J=2.0 Hz, 1H), 7.91 (t, J=1.3 Hz, 1H), 7.78 (t, J=1.5 Hz, 1H), 7.36-7.7.31 (m, 2H), 7.05-7.00 (m, 2H), 6.67 (d, J=7.5 Hz, 1H), 5.25 (q, J=7.1 Hz, 1H), 3.34 (s, 3H), 2.87 (s, 3H), 1.59 (d, J=7.0 Hz, 3H). LCMS [M+H]+=376.
Reaction SMILES: [N:1]1[CH:6]=[N:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Li+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:23]=[C:22]2[CH2:33][C:34]([O-])=[O:35])=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:23]=[C:22]2[CH2:33][C:34]([N:10]2[CH2:9][CH2:8][N:7]([C:2]3[N:3]=[CH:4][N:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)=[O:35])=[CH:19][CH:20]=1
Reactant: c1ncnc(N2CCNCC2)n1
Reactant: O=C([O-])Cc1nc(-c2ccc(F)cc2)cn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1nc(-c2ccc(F)cc2)cn1-c1ccc(F)cc1)N1CCN(c2ncncn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
22 mg 1-(1,3,5-triazin-2-yl)-piperazine was added to 40 mg (1,4-bis-(4-fluoro-phenyl)-1H-imidazol-2-yl)-acetic acid lithium salt, 45 mg TBTU, 0.03 mL DIPEA in 0.75 mL DMF. The reaction was stirred overnight at RT. 5 mL water was added to the reaction and the mixture was stirred 1 h. The precipitate was filtered and dried to give 37 mg desired product.
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[C:22]3[C:17](=[N:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]([CH2:24][CH3:25])[C:15](=[O:26])[C:14]=2[CH2:27][CH2:28][CH2:29][OH:30])[CH:10]=[CH:11][CH:12]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(N(CC)CC)C>[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[C:22]3[C:17](=[N:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]([CH2:24][CH3:25])[C:15](=[O:26])[C:14]=2[CH2:27][CH2:28][CH2:29][O:30][S:32]([CH3:31])(=[O:34])=[O:33])[CH:10]=[CH:11][CH:12]=1
Reactant: CCn1c(=O)c(CCCO)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1c(=O)c(CCCOS(C)(=O)=O)c(-c2cccc(Cl)c2)c2ccc(C)nc21

Procedure:
To a THF solution of 4-(3-chlorophenyl)-1-ethyl-3-(3-hydroxypropyl)-7-methyl-1,8-naphthyridin-2(1H)-one were added triethylamine and methanesulfonyl chloride, followed by reaction under heating. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 4-(3-chlorophenyl)-1-ethyl-3(3-methanesulfonyloxypropyl)-7-methyl-1,8-naphthyridin-2(1H)-one. NMR1: 4.67 (2H, q, J=7.1 Hz), 4.18 (2H, t, J=6.3 Hz), 2.93 (3H, s).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH2:12]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]([CH3:15])[CH3:14].C([O-])(=O)C.[Na+]>O>[CH2:20]([O:19][C:17]([C:16]1[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:3][NH:2][C:12]=1[CH:13]([CH3:15])[CH3:14])=[O:18])[CH3:21]
Reactant: CCOC(=O)CCC(C)C
Reactant: NCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1c(-c2ccccc2)c[nH]c1C(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
A mixture of 2-aminoacetophenone hydrochloride (1 equiv.), ethyl isobutylacetate (1.2 equiv.) and sodium acetate (2.4 equiv.) in H2O was stirred at 100° C. for 18 hours and then cooled to room temperature. The aqueous layer was decanted off and the oil was dissolved in ethyl acetate. It was then washed with water and brine and then dried to give (93%) of 2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester as a red brown oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([CH2:10]O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.P(Br)(Br)[Br:13]>C(OCC)C>[Br:13][CH2:10][C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[CH:2][S:1][C:5]=2[CH:6]=1
Reactant: OCc1ccc2ncsc2c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: BrCc1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Dissolve benzothiazol-6-yl-methanol (0.4 g, 2.55 mmol) in diethyl ether (10 mL) and add slowly a solution of phosphorus tribromide (0.7 g, 2.55 mmol) in diethyl ether (5 mL). Stir the reaction mixture for 2 h at ambient temperature, wash with brine, dry the organic phase over anhydrous Na2SO4, evaporate the solvent and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1 and 4:1) to obtain the title compound as a white solid (0.5 g, 86%). MS (ES+) m/z: 229 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]2[C:17](=[O:18])[N:16]([CH2:19][C:20]([N:22]3[C:28]4[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:27]=4[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:15]3[CH:35]=[CH:36][CH:37]=[CH:38][C:14]=3[N:13]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:12]2=[O:45])=[N:2]1>C(OCC)(=O)C.[Pd]>[CH3:34][O:33][C:32]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][N:22]([C:20](=[O:21])[CH2:19][N:16]3[C:15]4[CH:35]=[CH:36][CH:37]=[CH:38][C:14]=4[N:13]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:12](=[O:45])[C@H:11]([CH2:10][C:3]4[C:4]5[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=5[NH:1][N:2]=4)[C:17]3=[O:18])[C:28]=2[CH:29]=[CH:30][CH:31]=1
Reactant: COc1cccc2c1CCCCN2C(=O)CN1C(=O)[C@@H](Cc2n[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cccc2c1CCCCN2C(=O)CN1C(=O)[C@@H](Cc2n[nH]c3c2CCCC3)C(=O)N(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 16.5 %

Procedure:
A solution of (3R)-3-(1H-indazol-3-ylmethyl)-1-[2-(6-methoxy-2,3,4,5-tetrahydro-1H -1-benzazepin-1-yl)-2-oxoethyl]-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (32 mg) in ethyl acetate (4 mL) was treated with 10% palladium on charcoal (300 mg). Placed under H2 environment (by balloon) and stirred at room temperature for 48 hours. Filtered through celite and concentrated to dryness. Chromatographed on silica gel (Hexane:Ethyl Acetate). Lyophilized the residue to yield the title compound as a white solid (5.3 mg)
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].O[C@@H:6]1[C@H:12]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:9]2([CH2:10][CH3:11])[C:8](=[O:26])[CH2:7]1)[C@@H:21]1[C:16](=[CH:17][C:18](=[O:25])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3.C(OC(=O)C)(=O)C>>[CH3:11][CH2:10][C@:9]12[CH2:24][CH2:23][C@H:22]3[C@@H:13]([CH2:14][CH2:15][C:16]4[C@@H:21]3[CH2:20][CH2:19][C:18](=[O:25])[CH:17]=4)[C@@H:12]1[C@@H:6]([O:2][N+:1]([O-:4])=[O:3])[CH2:7][C:8]2=[O:26]
Reactant: O=[N+]([O-])O
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](O)CC2=O
Solvent: CC(=O)OC(C)=O
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](O[N+](=O)[O-])CC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At -20° C., 6 ml. of concentrated nitric acid is added dropwise to 8.0 g. of 15α-hydroxy-18-methyl-4-estrene-3,17-dione in 60 ml. of acetic anhydride. After 1 hour, the reaction solution is introduced into ice/water. The thus-precipitated product is vacuum-filtered, washed several times with water, taken up in methylene chloride, and dried over sodium sulfate. After chromatographing the crude product on silica gel with acetone-hexane, 6.4 g. of 18-methyl-15α-nitrooxy-4-estrene-3,17-dione is produced.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:10]=1[CH2:11][NH:12][C:13]1[N:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>O1CCCC1>[NH2:16][CH2:15][C:14]1[C:13]([NH:12][CH2:11][C:10]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:9]=2[O:8][CH3:7])=[N:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(CNc2ncccc2C#N)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncccc2CN)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.7 %

Procedure:
Lithium aluminum hydride (1.0 M in THF, 11.4 mL, 11.4 mmol) was added slowly to a solution of 2-[(2,4-dimethoxybenzyl)amino]nicotinonitrile (2.80 g, 10.4 mmol) in tetrahydrofuran (35 mL) at 0° C. The reaction was allowed to warm to room temperature and stir for 4 h. The reaction was carefully quenched with a saturated aqueous solution of sodium sulfate, filtered with copious dichloromethane and concentrated to produce the title compound (2.92 g). MS 274.3 (M+1).