Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Si:25]([O:32][CH2:33]C)([O:29][CH2:30]C)[O:26][CH2:27]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Si:25]([O:32][CH3:33])([O:26][CH3:27])[O:29][CH3:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO[Si](CCCCCCCCCCCCCCCCCCc1ccccc1)(OCC)OCC
Agent: Cl
Solvent: CO
Product: CO[Si](CCCCCCCCCCCCCCCCCCc1ccccc1)(OC)OC

Procedure:
The 18-phenyl octadecyl triethoxysilane obtained was subjected to alcohol exchange reaction in methanol having a small quantity of hydrochloric acid dissolved therein to obtain 6.5 g of 18-phenyl octadecyl trimethoxysilane. The purity by HPLC was 89.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[C:4]([CH3:10])[CH:3]=1.[C-:11]#[N:12].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:11]#[N:12])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1CCl
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(Cl)ccc1CC#N
Yield: 72.5 %

Procedure:
Step B In a manner similar to the method described in Example 57 Step B, 4-chloro-2-methylbenzyl chloride (1.83 g, 10 mmol) was reacted with KCN (1.76 g, 27 mmol) in ethanol (13 mL) and water (10 mL) at 100° C. for 1 h to give 4-chloro-2-methylbenzyl cyanide as a yellow oil (1.2 g, 69%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([OH:36])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[Br:38][CH2:39][CH2:40][CH2:41]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([O:36][CH2:41][CH2:40][CH2:39][Br:38])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: BrCCCBr
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCBr)cc(N(CC(=O)OC)CC(=O)OC)c1
Yield: 71 %

Procedure:
A mixture of 4.0 g (7.67 mmol) of N-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 7.8 ml (76.6 mmol) of 1,3-dibromopropane and 5.3 g (38.3 mmol) of potassium carbonate in 75 ml of acetone and 15 ml of DMF was stirred at reflux under argon for 41 hours. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated to a solid which was purified by HPLC using 5% ethyl acetate-toluene to give 3.5 g (72% yield, mp 67°-69°) of N-[3-(3-bromopropoxy)-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl) glycine methyl ester. The structure was confirmed by the nmr spectrum.
Reaction SMILES: C([O:4][C:5](=[O:18])[C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:8][CH:7]=1)(C)C>Cl>[CH:13]1([C:9]2[C:10]([CH3:12])=[CH:11][C:6]([C:5]([OH:18])=[O:4])=[CH:7][N:8]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Cc1cc(C(=O)OC(C)C)cnc1C1CCCC1
Agent: Cl
Product: Cc1cc(C(=O)O)cnc1C1CCCC1

Procedure:
A solution of 6-cyclopentyl-5-methyl-nicotinic acid isopropyl ester (138 mmol, 558 μmol) in 25% aq. HCl (5 mL) is stirred at 65° C. for 24 h. The solvent is evaporated and the residue is dried under HV to give the title compound as a hydrochloride salt (163 mg) in form of a beige solid; LC-MS: tR=0.64 min; [M+1]+=206.50.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][C:8](=[O:23])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:10]=1)[CH3:2].[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][C:8](=[O:23])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][Br:25])=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:10]=1)[CH3:2]
Reactant: BrCCCCCBr
Reactant: CCOC(=O)CCCC(=O)c1ccc(O)c(CCC(=O)OCC)c1
Product: CCOC(=O)CCCC(=O)c1ccc(OCCCCCBr)c(CCC(=O)OCC)c1
Yield: 85.7 %

Procedure:
Starting with 0.332 g (0.99 mmol) of 3-(3-ethoxy-3-oxopropyl)-4-hydroxy-δ-oxobenzenepentanoic acid ethyl ester, and 1.16 g (5.04 mmol) of 1,5-dibromopentane, the title compound was obtained in 85.7% yield as a white solid, mp 48°-49° C., using the procedure of example 21.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:24][N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:28]3[CH2:29][CH2:30][CH2:31][N:25]([CH3:24])[CH2:26][CH2:27]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Reactant: CN1CCCNCC1
Product: CN1CCCN(c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cn2)CC1

Procedure:
50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide was reacted with 1-methyl-1,4-diazepane via Procedure F. The reaction was evaporated to dryness and purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-methyl-1,4-diazepan-1-yl)nicotinamide. MS (Q1) 422 (M)+.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:18]([N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: c1cnc2c(c1)CNCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2ncccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-1,6-naphthyridine [Shiozawa et al Chem. Pharm. Bull., 32, 2522 (1984)] (4.9 g, 0.037 mol) in dichloromethane at 0° C. was added triethylamine (6.1 ml, 0.044 mol) and acetyl chloride (3.11 ml, 0.044 mol) dropwise and the reaction was allowed to warm to room temperature and stirred for a further 18 hours. The reaction mixture was partitioned between water and dichloromethane, the layers were separated and the aqueous layer was extracted twice more with dichloromethane. The combined organic layers were dried over MgSO4 and evaporated under reduced pressure to afford a residue which was purified on silica gel, eluting with 0.880 aqueous ammonia:methanol:dichloromethane (0.5:3.5:96, v/v). This afforded the title compound (58%) as an oil. Rf 0.60 (0.880 aqueous ammonia:methanol:dichloromethane, 2:14:84, v/v). 1H NMR (CDCl3): δ=2.15 (3H, s), 3.04 (2H, m), 3.75 and 3.90 (2H, 2×m), 4.60 and 4.70 (2H, 2×s), 7.10 (1H, m), 7.42 (1H, m), 8.42 (1H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[N:9]=2)[CH:3]=1.[CH3:29][N:30](C)C=O>COC(C)(C)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:17]([N:14]1[CH2:15][CH2:16][C:11]2[N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([CH:7]=[CH:6][N:5]=3)[C:29]#[N:30])[C:12]=2[CH2:13]1)(=[O:19])[CH3:18]
Reactant: CC(=O)N1CCc2c(c(-c3cc(Br)ccn3)nn2Cc2ccc(F)cc2F)C1
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]
Solvent: COC(C)(C)C
Product: CC(=O)N1CCc2c(c(-c3cc(C#N)ccn3)nn2Cc2ccc(F)cc2F)C1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a solution of Zn(CN)2 (39 mg, 0.335 mmol) and tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol) in dry N,N-dimethylformamide (0.6 ml) at 150° C. was slowly added a solution of 1-[3-(4-Bromo-pyridin-2-yl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (6j) (0.15 g, 0.335 mmol) in dry N,N-dimethylformamide (1 ml). The mixture was stirred at 150° C. for 3 h and then at 25° C. for 16 h. The mixture was diluted with methyl-tert-butylether, filtrated over Celite, washed with water, dried over Na2SO4, filtrated and evaporated to dryness. The residue was suspended in methanol, and the solid was filtrated off to give 67 mg of 2-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-isonicotinonitrile (13a).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][NH:16]4)=[C:12]([NH:19][C:20]([C:22]4[C:27]([C:28]([CH3:30])=[CH2:29])=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:21])[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>C(O)C.[Pd]>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][NH:16]4)=[C:12]([NH:19][C:20]([C:22]4[C:27]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:21])[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C=C(C)c1cccnc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cccnc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Yield: 10.2 %

Procedure:
N-[6-(1H-Indol-4-yl)-1H-indazol-4-yl]-3-(1-methylethenyl)-2-pyridinecarboxamide (166 mg, 0.42 mmol, prepared as described in Example 62) was dissolved in ethanol and hydrogenated at 25° C. on the H-cube using a 5% palladium on carbon catalyst. The mixture was passed through the flow reactor twice then the catalyst was replaced before the mixture was passed through another two times. The solvent was removed in a stream of nitrogen to give a pale yellow oil. This was purified by mass-directed automated preparative HPLC (Method B) to give the title compound (17 mg) as a white solid.
Reaction SMILES: C[Mg]Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][C:14]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)([C:17]#N)[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH4+].[Cl-]>C1COCC1>[CH2:4]([N:11]1[CH2:16][CH2:15][C:14]([N:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)([CH3:17])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CC1(N2CCNCC2)CCN(Cc2ccccc2)CC1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(N2CCNCC2)CCN(Cc2ccccc2)CC1
Reaction time: 3 h

Procedure:
15 mL methylmagnesium chloride solution (45 mmol, 3 M in THF) were added at RT to 2.37 g (7.92 mmol) 1-benzyl-4-piperazin-1-yl-piperidine-4-carbonitrile in 100 mL dry THF and the reaction mixture was stirred for 3 h. Saturated NH4Cl solution was added, the mixture was stirred for another 10 min, the aqueous phase was washed with EtOAc, combined with 4 M NaOH solution until an alkaline reaction was obtained, extracted exhaustively with DCM and the combined organic phases were dried over Na2SO4. After elimination of the desiccant and solvent the residue was further reacted without any further purification.
Reaction SMILES: C([N:4]1[CH:11]2[CH2:12][N:7]([C:8]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:9]=3[CH2:10]2)[CH2:6][CH2:5]1)(=O)C.[ClH:20]>>[ClH:20].[N+:17]([C:15]1[CH:14]=[CH:13][C:9]2[CH2:10][CH:11]3[CH2:12][N:7]([C:8]=2[CH:16]=1)[CH2:6][CH2:5][NH:4]3)([O-:19])=[O:18]
Reactant: CC(=O)N1CCN2CC1Cc1ccc([N+](=O)[O-])cc12
Agent: Cl
Product: O=[N+]([O-])c1ccc2c(c1)N1CCNC(C2)C1

Procedure:
A mixture of 4-acetyl-9-nitro-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (37.5 g.) and concentrated hydrochloric acid (200 ml.) was heated for four hours on a steam bath, then concentrated. The solid residue was slurried with ethanol (100 ml.) and filtered affording 9-nitro-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine hydrochloride (30 g., m.r. 255°-260° C.), the hydrochloride salt of the compound of Formula III wherein Q* is hydrogen. The salt was converted with dilute aqueous sodium hydroxide into the free base, a syrupy brown oil (17.5 g.).
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.C(OC([NH:37][C:38]1[S:42][C:41]([C:43]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([O:50][CH3:51])[C:44]=2[F:52])=[N:40][C:39]=1[C:53](O)=[O:54])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[NH2:37][C:38]1[S:42][C:41]([C:43]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([O:50][CH3:51])[C:44]=2[F:52])=[N:40][C:39]=1[C:53]([NH:29][C:12]1[C:13]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH2:21])[CH2:15]2)=[C:8]2[CH2:7][CH2:6][CH:5]([OH:4])[C:9]2=[N:10][CH:11]=1)=[O:54]
Reactant: COc1ccc(F)c(-c2nc(C(=O)O)c(NC(=O)OC(C)(C)C)s2)c1F
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
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: CO
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)C[C@H](N)C3)CCC4O)c(N)s2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.5 %

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (10.0 mg, 0.025 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxylic acid (9.6 mg, 0.025 mmol), HATU (23.5 mg, 0.062 mmol) in DMF (0.06 mL) and DIPEA (0.013 mL, 0.074 mmol) was stirred at room temperature for 3 h. The mixture was diluted with MeOH and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a white powder (5.5 mg, 29%). LCMS calc. for C37H47F2N6O8S (M+H)+: m/z=773.3. Found: 773.3.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][C:16]1[C:17]([NH:28]C(OC(C)(C)C)=O)=[N:18][N:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>C(Cl)(Cl)Cl.CCOC(C)=O>[NH2:28][C:17]1[C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:20][N:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[N:18]=1
Reactant: CC(C)(C)OC(=O)Nc1nn(-c2ccccc2F)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nn(-c2ccccc2F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.3 %

Procedure:
TFA (2 mL) was added to a solution of 4-benzyloxy-3-(tert-butoxycarbonyl)amino-1-(2-fluorophenyl)pyrazole (1.30 g) in CHCl3 (5 mL) at room temperature and the mixture was stirred for 1.5 hours at room temperature. After being neutralized with 5N NaOH, the mixture was diluted with EtOAc and washed with H2O, sat. NaHCO3 and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The semicrystalline residue was triturated with hexane overnight and filtered to yield 742.6 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.S([O-])([O-])(=O)=[O:14].[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+].C(O)(C)C>CC(C)=O.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[C:6](=[O:14])[CH2:7][C:8]2([CH3:12])[CH3:11]
Reactant: CC1(C)CCc2ccc(Cl)cc21
Reactant: O=S(=O)([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)CC(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-chloro-1,1-dimethylindane (2.19 g, 0.0121 mol) was dissolved in acetone (50 mL), and 1.41 M solution of magnesium sulfate in water (9.02 mL) was added, followed by potassium permanganate (3.83 g, 0.0242 mol). The mixture was stirred at room temperature overnight. 1:1 water:isopropanol was then added to the mixture and this was stirred for 1 hour. The mixture was then evaporated to an aqueous residue and ethyl acetate was added. The mixture was filtered, washing the collected solids with EtOAc, and the filtrates were separated. The organic phase was concentrated, and the residue was purified by silica gel chromatography, eluting with 20 to 100% dichloromethane in hexanes to yield the product, 1.25 g (46%). 1H-NMR (400 MHz, CDCl, δ) 7.62 (d, J=8.3 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.34 (dd, J=1.8 Hz, 8.1 Hz, 1H), 2.60 (s, 2H), 1.42 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C@@H:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17]([CH3:26])([CH3:25])[O:16][C:15]3=[O:27])=[CH:10][CH:9]=2)=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Cl[C:38]1[N:43]=[C:42]([C:44]#[N:45])[CH:41]=[CH:40][N:39]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:25][C:17]1([CH3:26])[O:16][C:15](=[O:27])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[C:5]([C:38]4[N:43]=[C:42]([C:44]#[N:45])[CH:41]=[CH:40][N:39]=4)[CH:4]=[N:3][C:2]=3[F:1])=[CH:9][CH:10]=2)[C@H:18]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1(C)OC(=O)N(c2ccc(-c3cc(B4OC(C)(C)C(C)(C)O4)cnc3F)cc2)[C@H]1c1ccccc1
Reactant: N#Cc1ccnc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-c3cc(-c4nccc(C#N)n4)cnc3F)cc2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A microwave vial was charged with (S)-3-(4-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.074 g, 0.152 mmol), 2-chloropyrimidine-4-carbonitrile (commercially available from Synthonix, Wake Forest, N.C.)(0.023 g, 0.167 mmol), sodium carbonate (0.048 g, 0.455 mmol), dioxane (2.0 mL), and water (0.400 mL). Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) DCM adduct (0.012 g, 0.015 mmol) was added, the system was purged with argon, and the tube was sealed. The mixture was then stirred at 100° C. in a microwave for 1 hour. The resulting reaction mixture was filtered through Celite® brand filter aid and the filtrate was concentrated to afford a brown solid. The resulting solid was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-50% EtOAc-hexane) to afford (S)-2-(5-(4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)phenyl)-6-fluoropyridin-3-yl)pyrimidine-4-carbonitrile (0.051 g, 0.110 mmol, 72.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (s, 3H), 1.66 (s, 3H), 5.53 (s, 1H), 7.14-7.50 (m, 5H), 7.59-7.78 (m, 4H), 8.17 (d, J=4.99 Hz, 1H), 8.78 (dd, J=9.68, 2.35 Hz, 1H), 9.09 (dd, J=2.30, 0.93 Hz, 1H), 9.29 (d, J=4.89 Hz, 1H). m/z (ESI) 466 (M+H)+.
Reaction SMILES: [C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([OH:3])=[O:2].OS(O)(=O)=O>C(O)CCC>[C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([O:3][CH2:7][CH2:6][CH2:14][CH3:13])=[O:2]
Reactant: O=C(O)C=Nc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCCCOC(=O)C=Nc1cc(Cl)ccc1C(=O)O
Temperature: 75 °C
Yield: 151.4 %

Procedure:
5 g (21.8 mmol) of N-carboxymethylene-4-chloro-anthranilic acid are dissolved in 40 ml of n-butanol. 108 mg (1.05 mmol) of concentrated H2SO4 are added and the mixture is heated at 75° C. for 2 hours. After cooling to room temperature, the product which has precipitated out is filtered off with suction, washed with n-butanol and dried. 4.7 g (16.5 mmol; 76%) of pale yellow crystalline N-carbobutoxymethylene-4-chloro-anthranilic acid are obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.CC1C=CC(C[O:18][C:19](=O)[O:20][N:21]2[C:25](=[O:26])[CH2:24][CH2:23][C:22]2=[O:27])=CC=1>>[O:27]=[C:22]1[CH2:23][CH2:24][C:25](=[O:26])[N:21]1[O:20][C:19](=[O:18])[O:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:9][CH:8]=1
Reactant: OCc1ccc(C2CC2)cc1
Reactant: Cc1ccc(COC(=O)ON2C(=O)CCC2=O)cc1
Product: O=C(OCc1ccc(C2CC2)cc1)ON1C(=O)CCC1=O

Procedure:
The title compound was prepared from (4-cyclopropyl-phenyl)-methanol as described for similar compounds previously (Chem. Pharm. Bull., 38(1):110–115(1990) and INTERMEDIATE 1A).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl>C(O)C>[ClH:25].[Br:1][C:2]1[S:3][C:4]([Br:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:8]1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Br)sc1Br)C2
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(Br)sc1Br)C2
Temperature: 90 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
To a mixture of 7-(2,5-dibromothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.08 g) and aminoguanidine hydrochloride (24 mg) were added ethanol (1 ml) and concentrated hydrochloric acid (0.04 ml), and the mixture was stirred at 90° C. for 12 hours and cooled. Precipitated crystals were filtered, washed with ethanol and dried to give 7-(2,5-dibromothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 124) (0.09 g) as pale yellow crystals.
Reaction SMILES: ClC1C=C2C(=CC=1)NC(C(N[C@@H]1CC3C(=CC=CC=3)NC1=O)=O)=C2.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30]([C:35]([NH:37][C@H:38]1[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]([CH2:48][C:49]#[N:50])[C:39]1=[O:51])=[O:36])=[CH:29]2.ClC1C=C2C(=CC=1)NC(C(N[C@H]1CC3C(=CC=CC=3)NC1=O)=O)=C2>>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30]([C:35]([NH:37][C@@H:38]1[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]([CH2:48][C:49]#[N:50])[C:39]1=[O:51])=[O:36])=[CH:29]2
Reactant: N#CCN1C(=O)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Agent: O=C(N[C@@H]1Cc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C(N[C@H]1Cc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Product: N#CCN1C(=O)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21

Procedure:
The title compound was prepared from (R)-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril (Example 3) by the procedures described for the preparation of (S)-3-(5-chloroindole-2-carbonylamino)-1-cyanomethyl-3,4-dihydrocarbostyril (Example 17) from (S)-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril. HPLC/MS [M+H]+, 379.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[C:45]([CH3:47])[N:44]=[C:43]([CH3:48])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[C:43]([CH3:48])[N:44]=[C:45]([CH3:47])[CH:46]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (374 mg, 1.0 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (325 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (510 mg, 82%).