Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][NH2:35])[CH2:28]1)[CH2:24][CH3:25])[CH3:22]>C(#N)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11]([NH:35][CH2:34][CH2:33][N:29]3[CH2:30][CH2:31][CH2:32][CH:27]([CH2:26][N:23]([CH2:21][CH3:22])[CH2:24][CH3:25])[CH2:28]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Reactant: CCN(CC)CC1CCCN(CCN)C1
Solvent: CC#N
Product: CCN(CC)CC1CCCN(CCNC(=O)N2c3cc(Cl)ccc3C(=O)Nc3cccnc32)C1
Yield: 73 %

Procedure:
Prepared analogously to Example 46 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[(diethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 73% of theory. Colourless crystals, m.p. 125° C. (D.) (acetonitrile).
Reaction SMILES: B.O1CCCC1.[F:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[N:25]=[C:24]([C:27]([F:30])([F:29])[F:28])[S:23][C:22]=3[NH:21][C:20]3[CH:31]=[CH:32][CH:33]=[CH:34][C:19]=3[N:18]=2)[CH2:13][C@@H:12]1[CH2:35][CH2:36][O:37][CH3:38])=O.CO.C(N)CN>O1CCCC1.O.ClCCl>[F:7][CH2:8][CH2:9][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[N:25]=[C:24]([C:27]([F:30])([F:29])[F:28])[S:23][C:22]=3[NH:21][C:20]3[CH:31]=[CH:32][CH:33]=[CH:34][C:19]=3[N:18]=2)[CH2:13][C@@H:12]1[CH2:35][CH2:36][O:37][CH3:38]
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1C(=O)CF
Agent: B
Solvent: ClCCl
Solvent: O
Solvent: NCCN
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1CCF
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Add a solution of borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran; 3.8 mL, 3.8 mmol) to a 0° C. solution of (S)-2-fluoro-1-[2-(2-methoxy-ethyl)-4-(2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-1-yl]-ethanone (0.18 g, 0.38 mmol) in anhydrous tetrahydrofuran (3 mL) and stir at 0° C. for 3 hours. Quench the reaction, in an ice/water bath, slowly with methanol. Concentrate the reaction under reduced pressure and reconstitute in anhydrous dichloroethane (6 mL). Add ethylenediamine (0.23 mL, 3.4 mmol) and reflux for 45 minutes. Cool the reaction to ambient temperature and dilute with deionized water and dichloromethane (20 mL each). Separate the organic layer and extract the aqueous layer with dichloromethane (2×). Wash the combined organics with deionized water and then a saturated solution of sodium chloride, and then dry (sodium sulfate), filter, and concentrate under reduced pressure to an orange oil (0.19 g). Purify the oil by flash chromatography, eluting with a gradient of a solution of ethyl acetate:hexane (1:1, 0-50% in hexane over 45 minutes, then 100% for 13 minutes) to give the title compound: 0.050 g (29%). Mass spectrum (APCI+, m/e): 458 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:28])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26]Br)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[ClH:29].[C:30]1([C:36]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[ClH:29].[CH3:1][C:2]1[NH:3][C:4]([CH3:28])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][N:39]2[CH2:40][CH2:41][C:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:37][CH2:38]2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCBr)C1c1cccc([N+](=O)[O-])c1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 86.4 %

Procedure:
A mixture of 13 g of 3-methyl 5-(3-bromopropyl) (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 7.85 g of 4,4-diphenylpiperidine hydrochloride and 12 g of potassium carbonate in 120 ml of toluene and 25 ml of water is refluxed for 14 h under a nitrogen atmosphere and with vigorous stirring. After cooling, the phases are separated; the organic phase is washed twice with water, dried over sodium sulphate and evaporated in vacuo. The oily residue is dissolved in 140 ml of dioxane, after which 2.3 ml of concentrated hydrochloric acid solution (12.5 M, d=1.19) are added and 20-25 ml of the solvent mixture are then distilled off in vacuo. On standing at room temperature, the product crystallises spontaneously or after trituration and is filtered off under suction after 16 h, washed with dioxane and diisopropyl ether and dried in vacuo at 80° C. 16 g of the title compound of m.p. 158°-160° C. and [α]22D =+14.4° (c=1, methanol) are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[NH:15][C:12]2=[CH:13][N:14]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[S:52]1[CH:56]=[CH:55][C:54]([C:57](O)=[O:58])=[CH:53]1>CN(C=O)C.C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH:21][C:57]([C:54]3[CH:55]=[CH:56][S:52][CH:53]=3)=[O:58])=[O:19])[NH:15][C:12]2=[CH:13][N:14]=1
Reactant: NNC(=O)c1cc2cc(Cl)ncc2[nH]1
Reactant: O=C(O)c1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NNC(=O)c1cc2cc(Cl)ncc2[nH]1)c1ccsc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid hydrazide trifluoroacetic acid salt (Preparation 10—route 1, 0.110 g, 0.34 mmol) in DMF (3 mL) was added DIPEA (170.0 μL, 1.02 mmol). To the stirred solution, HOBt (0.046 g, 0.34 mmol), EDCI (0.078 g, 0.41 mmol), DIPEA (120.0 μL, 0.68 mmol) and thiophene-3-carboxylic acid (0.044 g, 0.34 mmol) were added. The reaction mixture was stirred at rt for 16 h and then concentrated in vacuo to give an oil. On addition of ethyl acetate to the oil, a solid precipitated. The solid was filtered and dried to give the title compound. m/z (ES+)=321 [M+H]+; RT=2.84 min.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][NH:8]2.[C:24]1([CH2:30][C:31](O)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.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>O>[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:31](=[O:32])[CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Cn1cc(-c2ccc3c(c2F)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cc(-c2ccc3c(c2F)CCN3C(=O)Cc2ccccc2)c2c(N)ncnc21
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A solution of 5-(4-fluoro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (100 mg, 0.281 mmol), Phenylacetic acid (38.2 mg, 0.281 mmol), HATU (107 mg, 0.281 mmol), DIEA (0.196 mL, 1.123 mmol) was stirred at room temperature for 3 days. The resulting suspension was poured into water (10 mL) and stirred for 30 min, and a precipitate formed. The precipitate was collected by filtration, and the residue was washed with water, then dried at the pump for an hour, then adsorbed onto silica and purified by flash chromatography (0-10% MeOH in EtOAc) to afford 5-[4-fluoro-1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80.2 mg, 71.2% yield) as a white solid. LC-MS (ES) m/z=402 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.24 (t, J=8.46 Hz, 2H), 3.74 (s, 3H), 3.89 (s, 2H), 4.29 (t, J=8.46 Hz, 2H), 5.79-6.20 (m, 2H), 7.10-7.42 (m, 7H), 7.95 (d, J=8.08 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH2:7][C:6]2=1)=O.Cl.[O:23]([NH2:25])[CH3:24].[OH-].[Na+]>>[CH3:24][O:23][N:25]=[CH:1][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH2:7][C:6]2=1
Reactant: O=Cc1ccc2[nH]c3c(c2c1)CC(NC(=O)C1CC1)CC3
Reactant: CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CON=Cc1ccc2[nH]c3c(c2c1)CC(NC(=O)C1CC1)CC3

Procedure:
Prepare the title compound from cyclopropanecarboxylic acid(6-formyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-amide (Preparation 72) (6.50 g, 57.3 mmol) methoxylamine hydrochloride (4.81 g, 57.6 mmol) and sodium hydroxide (1.84 g, 46.0 mmol), by essentially following procedures as described in Example 202 to obtain 6.00 g (84%) of product. MS (ES): m/z 312 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:28](Cl)(=[O:30])[CH3:29].C(N(C(C)C)CC)(C)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:28]([NH:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Sc3ccccc3)c(N)c2)CC1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Sc1ccccc1
Temperature: 25 °C
Yield: 102.3 %

Procedure:
A solution of tert-butyl 4-[3-amino-4-(phenylsulfanyl)phenyl]-1-piperazinecarboxylate (0.69 g, 1.6 mmol) in 7 mL of dry CH2Cl2 is cooled to 0° C. Acetyl chloride (0.13 mL, 1.8 mmol), diisopropylethylamine (0.32 mL, 1.8 mmol), and DMAP (0.020 g, 0.16 mmol) are added and the solution allowed to warm to rt overnight with stirring. Water and CH2Cl2 (10 mL each) are added and the layers separated. The aqueous layer is extracted with CH2Cl2 (3×10 mL) and the combined organic layers are washed with 1 N HCl, H2O, and brine. After drying over MgSO4, the mixture is filtered and concentrated to give the crude product. Purification by column chromatography (25% EtOAc/hexane) gives 0.70 g (99%) of the titel compound as a oil.
Reaction SMILES: Cl[C:2]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[C:5]([C:6]([NH:8][CH2:9][C@@H:10]([OH:27])[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[CH2:14][CH2:13]2)=[O:7])=[CH:4][N:3]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[Cl:25])[O:18][CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C@H:10]([OH:27])[CH2:9][NH:8][C:6](=[O:7])[C:5]2[C:28]([C:30]([F:32])([F:31])[F:33])=[CH:29][C:2]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[N:3][CH:4]=2)[CH2:13][CH2:14]1
Reactant: CS(N)(=O)=O
Reactant: O=C(NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1cnc(Cl)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)Nc1cc(C(F)(F)F)c(C(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)cn1
Yield: 8 %

Procedure:
A stirred solution of 6-chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-4-(trifluoromethyl)nicotinamide (0.28 g), methanesulfonamide (0.12 g) and potassium carbonate (0.148 g) in N-methyl-2-pyrrolidinone was heated under microwave irradiation (100 W) at 100° C. for 15 min. The reaction mixture was concentrated in vacuo and redissolved in 4:1:1 acetonitrile/water/acetic acid (6 mL) and subjected to RPHPLC (gradient 0.1% ammonium acetate/acetonitrile 95% to 5%) to yield a white solid (0.025 g).
Reaction SMILES: C(N(CC)C(=O)[O:5][C:6]1[C:15]([Cl:16])=[C:14]2[C:9]([CH2:10][CH2:11][N:12]([CH2:18][C:19]3[C:20]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])[C:13]2=[O:17])=[CH:8][CH:7]=1)C.[OH-].[Na+]>CCO>[CH2:28]([O:27][C:20]1[C:19]([CH2:18][N:12]2[CH2:11][CH2:10][C:9]3[C:14](=[C:15]([Cl:16])[C:6]([OH:5])=[CH:7][CH:8]=3)[C:13]2=[O:17])=[C:24]([CH3:25])[CH:23]=[C:22]([CH3:26])[N:21]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCN(CC)C(=O)Oc1ccc2c(c1Cl)C(=O)N(Cc1c(C)cc(C)nc1OCc1ccccc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)c(CN2CCc3ccc(O)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Yield: 86.5 %

Procedure:
A mixture of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl diethylcarbamate (1g, 14.0 g, 26.8 mmol) and NaOH (10.7 g, 268 mmol) in EtOH (200 mL) was refluxed overnight. The reaction mixture was concentrated under vacuum. To the reaction mixture was added H2O (200 mL) and the solution was acidified with 1 N HCl to pH 3. The reaction mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4 and concentrated under vacuum. To the residue was added EtOAc (20 mL) and petroleum ether (100 mL). The mixture was filtered and the solids were dried under vacuum to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (1 h, 9.8 g, 87%) as an off-white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[C:14]#[C:15][Si](C)(C)C.[NH2:20][C@@H:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])[CH3:22].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:26]([C:25]1[CH:24]=[C:23]([C@H:21]([N:20]2[C:2]3[C:3](=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([C:6]#[N:7])=[CH:8][CH:9]=3)[CH:14]=[CH:15]2)[CH3:22])[CH:30]=[CH:29][CH:28]=1)#[N:27]
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1C(F)(F)F
Reactant: C[C@@H](N)c1cccc(C#N)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C[C@H](c1cccc(C#N)c1)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 60 °C
Reaction time: 17 h
Yield: 41.1 %

Procedure:
An oven-dried vial was charged with 4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile (Example 21D) (0.173 g, 0.606 mmol), commercially available (R)-3-(1-aminoethyl)benzonitrile (0.098 g, 0.667 mmol) and K2CO3 (0.092 g, 0.667 mmol) and sealed with a rubber septum. Anhyd NMP (3 mL) was added via syringe and the mixture was stirred in a heating block at 60° C. under N2 for 17 h. The mixture was cooled, poured into satd NaHCO3 and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (R)-1-(1-(3-cyanophenyl)ethyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.0845 g, 41% yield) as a pale yellow gum which solidified upon trituration with Et2O/hexanes: 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=7.6 Hz, 1H), 7.57 (d, J=4.6 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.39 (d, J=8.6 Hz, 1H), 7.29 (d, J=6.7 Hz, 1H, overlapping with solvent), 6.96 (m, 1H), 5.76 (q, J=7.0 Hz, 1H), 2.01 (d, J=7.1 Hz, 3H); MS (LCMS ES+) m/z 340 ([M+H]+, 86%), 381 ({[M+H]+MeCN}+, 100%).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[CH:5][C:4]=1[OH:16])#[N:2].Cl.N1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:19]([C:21]12[CH2:7][CH2:8][C:3]([C:4]([O:16][C:4]3[CH:5]=[CH:6][C:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:8]([C:9]#[N:10])[C:3]=3[C:1]#[N:2])=[O:16])([CH2:19][CH2:20]1)[CH2:23][CH2:22]2)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: c1ccncc1
Reactant: CCCCCc1ccc(O)c(C#N)c1C#N
Agent: Cl
Product: CCCCCc1ccc(OC(=O)C23CCC(CCCCC)(CC2)CC3)c(C#N)c1C#N

Procedure:
25 mmoles of 4-pentylbicyclo(2,2,2)octane-1-carboxylic acid are warmed to the reflux temperature with 40 ml of thionyl chloride for 30 minutes. The acid chloride formed was freed from excess thionyl chloride. The acid chloride thus obtained was now added dropwise to a solution of 25 mmoles of 2,3-dicyano-4-pentylphenol (m.p. 142° C.) in 100 ml of pyridine at 80° C. When the reaction had ended, the mixture was poured into excess dilute hydrochloric acid and extracted with methylene chloride. The crude product obtained from the extract by evaporation was recrystallized. The resulting title compound of this example is monotropically nematic (K 84.0 N (36.1) I) and has a negative DCA.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:19][C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1>>[Cl:1][C:2]1[C:3](/[C:4](/[OH:6])=[CH:26]\[C:24]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:19])[N:25]=2)=[CH:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13](=[O:14])[O:15][CH2:16][CH:17]=[CH2:18]
Reactant: C=CCOC(=O)Nc1cccc(C(=O)OC)c1Cl
Reactant: Cc1ccnc(Cl)n1
Product: C=CCOC(=O)Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl
Yield: 79.6 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 5, Step B using methyl 2-chloro-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (30 g, 0.11 mol) and 2-chloro-4-methylpyrimidine (15.8 g, 0.12 mol) the title compound of Step B was prepared (29 g, 79.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.52-13.58 (br, 0.9H), 8.41-8.42 (m, 1H), 8.22-8.27 (m, 1H), 7.28-7.35 (m, 2.2H), 7.21-7.24 (m, 1.2H), 6.85-6.88 (m, 1H), 5.91-6.02 (m, 1H), 5.73 (s, 1H), 5.23-5.40 (m, 2H), 4.66-4.70 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]4([CH3:27])[C:24]([O-:26])=[O:25])[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.O.[Li+].[OH-]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]4([CH3:27])[C:24]([OH:26])=[O:25])[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C(=O)[O-])CCCCC1Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C(=O)O)CCCCC1Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (1R,3S)-methyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate, 52j, (0.035 g, 0.083 mmol) dissolved in MeOH (5 mL) and water (1 mL) was added LiOH (0.004 g, 0.168 mmol). The reaction was allowed to stir for 2 days at room temperature and then concentrated to dryness. The residue was washed with ethanol. The combined ethanol washings were concentrated in vacuo, yielding 30 mg of desired product as an off white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:11]=[C:5]2[N:4]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:3]1=[O:24].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:33]1([C:30]2[CH:31]=[CH:32][C:27]([CH2:26][N:10]3[C:9]([S:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[C:6]4[C:5]([N:4]([CH2:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:3](=[O:24])[N:2]([CH3:1])[C:7]4=[O:8])=[N:11]3)=[CH:28][CH:29]=2)[CH:37]=[N:36][CH:35]=[N:34]1
Reactant: Cn1c(=O)c2c(Sc3ccccc3)[nH]nc2n(CC(C)(C)C)c1=O
Reactant: BrCc1ccc(-n2cncn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(Sc3ccccc3)n(Cc3ccc(-n4cncn4)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude 5-methyl-7-neopentyl-3-(phenylthio)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (40 mg, 0.12 mmol), 1-(4-(bromomethyl)phenyl)-1H-1,2,4-triazole (28 mg, 0.12 mmol) and K2CO3 (16 mg, 0.12 mmol) are suspended in 5 mL of anhydrous DMF. The reaction mixture is stirred at room temperature overnight, and then evaporated to dryness under reduced pressure. The residue is purified by silica gel column chromatography to give pure product as white solids. MS (ESI) m/z 502.2 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30])[CH2:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[C:15](=[O:21])[CH2:14]1)=[O:12])=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C@H:9]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30])[CH2:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[C:15](=[O:21])[CH2:14]1)=[O:12]
Reactant: CN1CCCN(C(=O)C[C@@H](Cc2cc(F)ccc2F)NC(=O)OC(C)(C)C)CC1=O
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCCN(C(=O)C[C@H](N)Cc2cc(F)ccc2F)CC1=O
Reaction time: 4 h

Procedure:
(3R)-4-[(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,5-trifluorophenyl)butanoyl]hexahydro-3-methyl-2H-1,4-diazepin-2-one from Step E was treated with 4N hydrogen chloride in dioxane, stirred for 4 h and evaporated to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[C:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:3]1.Br[C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[N:32]([S:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)(=[O:51])=[O:50])[C:33]([C:35]3([OH:48])[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]3)=[CH:34][C:27]=12>>[OH:48][C:35]1([C:33]2[N:32]([S:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)(=[O:51])=[O:50])[C:28]3=[N:29][CH:30]=[CH:31][C:26]([C:5]4[C:4]([C:16]5[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=5)=[N:3][N:2]([CH3:1])[CH:6]=4)=[C:27]3[CH:34]=2)[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)CC1
Product: Cn1cc(-c2ccnc3c2cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 100 using 1-methyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 1,1-dimethylethyl 4-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-4-hydroxy-1-piperidinecarboxylate provided the title compound. ESMS [M+H]+: 659.2.
Reaction SMILES: [C:1]1(Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F-].[Cs+]>O1CCOCC1.CCCCCC.O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni]>[C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccccc1
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: C1=CCCC=CCC1
Product: c1ccc(-c2ccccc2)cc1
Yield: 26.1 %

Procedure:
A 100 mL of reactor equipped with magnetic stir bar was charged with 83.4 mg (0.303 mmol) of Ni(COD)2, 50.0 mg (0.308 mmol) of (t-Bu)2PH(O), 1.13 g (10.0 mmol) of Ph-Cl, 1.83 g (15.0 mmol) of PhB(OH)2 and 4.56 g (30.0 mmol) of CsF in 15 mL of 1,4-dioxane. The resulting mixture was refluxed for 20 h. The reaction was transferred to a separatory funnel, and diluted with 300 mL of hexane and 50 mL of H2O. The layers were separated, and organic layer was washed with H2O (2×100 mL), brine (100 mL), and dried over mgSO4, filtered, and the hexane and THF removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel using hexane as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to give 0.402 g (26% yield) of biphenyl.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH3:17][C:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:24]([C:18]3([CH3:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:25])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Reactant: CC1(C(=O)Cl)CCCCC1
Product: CCC(NC(=O)C1(C)CCCCC1)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 120 mg (0.74 mmol) 1-methylcyclohexanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.