Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[C:9](=O)[NH:10][CH:11]([C:12]([F:15])([F:14])[F:13])[C:5]=2[O:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:22]>C(Cl)Cl>[Cl:22][C:9]1[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH:11]([C:12]([F:15])([F:14])[F:13])[N:10]=1
Reactant: Cc1noc2c1-c1ccccc1C(=O)NC2C(F)(F)F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1noc2c1-c1ccccc1C(Cl)=NC2C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.7 %

Procedure:
To a round bottomed flask was added 1-methyl-4-(trifluoromethyl)-4H-benzo[c]isoxazolo[4,5-e]azepin-6(5H)-one (86 mg, 0.305 mmol), DCM (2 mL), and PCl5 (102 mg, 0.488 mmol). The solution was stirred at room temperature for 30 min before addition of more PCl5 (˜0.5 eq). The solution was stirred at room temperature for 4 h before pouring onto an ice-saturated aqueous NaHCO3 mixture. The layers were separated and the aqueous phase was extracted with DCM. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford the titled compound (52.9 mg, 0.176 mmol). LC/MS m/z 301 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:13]([C:15]#[N:16])=[CH:12][NH:11][C:10](=[O:17])[C:9]=3[C:8]([C:18]3[N:22](C4CCCCO4)[N:21]=[CH:20][CH:19]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:29].C(OCC)(=O)C>C(O)C>[ClH:29].[CH:1]1([N:6]2[C:14]3[C:13]([C:15]#[N:16])=[CH:12][NH:11][C:10](=[O:17])[C:9]=3[C:8]([C:18]3[NH:22][N:21]=[CH:20][CH:19]=3)=[CH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#Cc1c[nH]c(=O)c2c(-c3ccnn3C3CCCCO3)cn(C3CCCC3)c12
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1c[nH]c(=O)c2c(-c3ccn[nH]3)cn(C3CCCC3)c12

Procedure:
A solution of 1-cyclopentyl-4-oxo-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile and 4N hydrogen chloride/ethyl acetate solution (1.31 mL) in ethanol (2 mL) was stirred overnight at 50° C., and the solvent was evaporated under reduced pressure. The residue was crystallized from ethanol and diisopropyl ether to give the title compound (136 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[C:13]([CH2:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])#[N:14]>C(O)C.N1CCCCC1>[C:13]([C:15](=[CH:7][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[C:3]([OH:12])=[C:2]([Cl:1])[CH:9]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])#[N:14]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: N#CCC(=O)Nc1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C=C(C#N)C(=O)Nc2ccccc2)cc(Cl)c1O
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a solution of 5-chlorovanillin (728 mg, 3.9 mmol) and cyanoacetanilide (625 mg, 3.9 mmol) in ethanol (20 ml) were added 3 drops of piperidine, and the resulting mixture was refluxed for 2 hours. After cooling to room temperature, the resulting solid was filtered and washed with ethanol: water (1: 1) to give the objective 2-cyano-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propenanilide (950 mg, 74% in yield).
Reaction SMILES: [OH-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>O>[C:3]1([S:9][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)CSc1ccccc1
Temperature: 25 °C
Yield: 111.3 %

Procedure:
After 2.05 g of sodium hydroxide was dissolved in 50 ml of water, 5.65 g of thiophenol was added to the solution under ice cooling, and the mixture was stirred for a half hour at room temperature. Under ice cooling, 10.0 g of tert-butyl bromoacetate was added to the reaction mixture and the resulting mixture was reacted at room temperature for 3 hours. After completion of the reaction, the reaction mixture was extracted 3 times with ethyl acetate and the extract was washed with saturated sodium chloride aqueous solution. After the ethyl acetate layer was dried over sodium sulfate, ethyl acetate was distilled off to give 12.8 g of crude tert-butyl (phenylthio)acetate.
Reaction SMILES: O[CH:2]([CH:25]1[S:29][C:28](=[O:30])[NH:27][C:26]1=[O:31])[CH2:3][C@H:4]1[CH2:9][CH2:8][CH2:7][C@@H:6]([O:10][CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[O:15][C:16]=2[CH3:17])[CH2:5]1.C(N(CC)CC)C.S(Cl)(C)(=O)=O>ClCCl>[CH3:17][C:16]1[O:15][C:14]([C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[N:13][C:12]=1[CH2:11][O:10][C@@H:6]1[CH2:7][CH2:8][CH2:9][C@H:4]([CH2:3][CH:2]=[C:25]2[S:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])[CH2:5]1
Reactant: Cc1cccc(-c2nc(CO[C@@H]3CCC[C@H](CC(O)C4SC(=O)NC4=O)C3)c(C)o2)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(-c2nc(CO[C@@H]3CCC[C@H](CC=C4SC(=O)NC4=O)C3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
344 mg of 5-{1-hydroxy-2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}thiazolidine-2,4-dione are dissolved in 20 ml of dichloromethane, and 0.13 ml of triethylamine and and 0.12 ml of mesyl chloride are added. The mixture is stirred at room temperature for two hours, and another 0.13 ml of triethylamine and and 0.12 ml of mesyl chloride are added. The mixture is stirred at room temperature for 12 hours. 100 ml of dichloromethane are added, the mixture is washed with saturated sodium bicarbonate solution and dried over magnesium sulfate and the solvent is then removed under reduced pressure. The resulting residue is dissolved in 10 ml of tetrahydrofuran and, at −78° C., 0.22 ml of a 2.7 M solution of n-butyllithium in n-hexane is added. The mixture is stirred at 0° C. for 30 minutes, 20 ml of 1N hydrochloric acid are then added and the mixture is extracted three times with in each case 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 81 mg of 5-{2-[Cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethylidene}thiazolidine-2,4-dione as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[CH2:15][C:16]#[CH:17].C1COCC1>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:17][C:16]#[CH:15])(=[O:13])=[O:12])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)O)cc1
Reactant: C#CCBr
Solvent: C1CCOC1
Solvent: O
Product: C#CCS(=O)(=O)c1ccc(NC(C)=O)cc1
Yield: 86.4 %

Procedure:
199 g (1.0 mol) of 4-acetylaminobenzenesulfinic acid were dissolved in 1000 ml of water at pH 6, the solution was added dropwise to a solution of 140 g (1.1 mol) of 3-bromoprop-1-yne and 200 ml of THF at from 40° to 50° C., and the mixture was maintained at that temperature until the reaction had ended (check by TLC). The precipitate formed was filtered off with suction at about 10° C., washed neutral with water and dried, leaving 205 g of 4-acetylamino-1-(prop-1-yn-3-ylsulfonyl)benzene (melting point 175°-179° C.). ##STR26##
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]/[C:12](=[C:19]2\[C:20](=[O:31])[NH:21][C:22]3[C:27]\2=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]/[C:12](=[C:19]2\[C:20](=[O:31])[NH:21][C:22]3[C:27]\2=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)/[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(C(=O)O)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 8 from (Z)-3-[1-(4-methoxycarbonyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone and sodium hydroxide solution in methanol.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.S(Cl)(Cl)=O.[N:25]1([CH2:30][CH2:31][NH2:32])[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:32][CH2:31][CH2:30][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Reactant: NCCN1CCCC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Nc1ncnc2ccc(-c3cccc(C(=O)NCCN4CCCC4)c3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-benzoic acid 14 (100 mg, 0.39 mmol) in DCM (2 mL) was heated with thionyl chloride (0.11 mL, 0.77 mmol) at 80° C. for 1 hour, the mixture was cooled to room temperature and concentrated to dry, 2-pyrrolidin-1-ylethanamine (CAS 7154-73-6) (0.05 mL, 0.58 mmol) was then added, and was stirred overnight. The reaction mixture was purified with prep HPLC to give pure 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide 24. LC/MS (ESI+): m/z 363 (M+H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10][C:9]=3[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1.[F-].[K+].Cl>CN(C)C=O.O>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([O:17][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:16][CH2:15][C:14]=3[CH:13]=2)=[N:20][CH:21]=1)([O-:27])=[O:26]
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)C2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)C3)nc1

Procedure:
6-Phenyl-5,6,7,8-tetrahydro-naphthalen-2-ol (30 mg), 2-chloro-5-nitropyridine (21 mg) and potassium fluoride (23 mg) in dry dimethylformamide were heated at 120° C. until disappearance of the starting material. Water and 1 N HCl were added and the mixture extracted with ethyl acetate. Ethyl acetate was washed with brine and water, dried and evaporated. The product was recrystallised from toluene. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.4 Hz), 8.61 (dd, 1H, J 9.0, 2.5), 7.18-7.35 (m, 7H), 6.95-6.99 (m, 2H), 2.83-3.01 (m, 5H), 1.87-2.04 (m, 2H).
Reaction SMILES: [OH-].[NH4+:2].C(OC([NH:10][C@H:11]([C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([F:34])[CH:27]=3)=[CH:25][C:19]=2[N:18]=1)[C@@H:12]([CH3:16])[C:13](O)=[O:14])=O)(C)(C)C>C(Cl)Cl.C1CCCCC1>[NH2:10][C@H:11]([C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([F:34])[CH:27]=3)=[CH:25][C:19]=2[N:18]=1)[C@@H:12]([CH3:16])[C:13]([NH2:2])=[O:14]
Reactant: C[C@@H](C(=O)O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(-c3ccc(C#N)c(F)c3)ccc2[nH]1
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C[C@@H](C(N)=O)[C@H](N)c1nc2cc(-c3ccc(C#N)c(F)c3)ccc2[nH]1

Procedure:
The title compound was prepared according to Preparation 28 using ammonium hydroxide and (2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-[5-(4-cyano-3-fluorophenyl)-1H-benzimidazol-2-yl]-2-methylpropanoic acid (Preparation 32). The residue was sonicated in DCM:cyclohexane 5:1 to afford the boc protected amide intermediate. The residue was dissolved in 4M HCl in dioxane and stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue dissolved in MeOH and passed through an SCX cartridge eluting first with MeOH followed by 3M NH3 in MeOH. The residue was purified using silica gel column chromatography eluting with DCM:MeOH:NH3 (90:10:0.5) to afford the title compound (55 mg, 71%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)[CH:32]=[N:33][CH:34]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(Cl)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 54 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (5-chloropyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.61 min, m/z=479.1-481.0 [M+H]+, m/z=477.1-479.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.79 (m, 1H) 1.80-1.91 (m, 1H) 2.89 (d, 1H) 3.18-3.28 (m, 2H) 3.35-3.44 (m, 1H) 4.18-4.24 (m, 1H) 4.87 (d, J=3.42 Hz, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.83-7.88 (m, 2H) 8.03 (t, J=1.96 Hz, 1H) 8.08 (d, J=2.20 Hz, 1H) 8.58 (d, J=1.71 Hz, 1H) 8.64 (d, J=2.45 Hz, 1H) 8.78 (d, J=2.45 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[OH:26][C@H:27]1[CH2:31][NH:30][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28]1.[C:36]([O:40][C:41]([NH:43][CH:44]([C@H:48]([CH3:56])[CH2:49][CH:50]([CH3:55])[CH2:51][CH2:52][CH:53]=[CH2:54])[C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].CCN(CC)CC>C(Cl)Cl>[C:36]([O:40][C:41]([NH:43][C@@H:44]([C@H:48]([CH3:56])[CH2:49][CH:50]([CH3:55])[CH2:51][CH2:52][CH:53]=[CH2:54])[C:45]([N:30]1[CH2:31][C@H:27]([OH:26])[CH2:28][C@H:29]1[C:32]([O:34][CH3:35])=[O:33])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.5 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 31.7 g, 83 mmol) was added to a solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate HCl (16.68 g, 92 mmol), (3R)-2-((tertbutoxycarbonyl)amino)-3,5-dimethylnon-8-enoic acid (25 g, 83 mmol) and NEt3 (34.9 mL, 250 mmol) in DCM (250 mL) and stirred at RT for 16 h. The reaction was washed with 1N HCl (3×) and then brine. The organics were dried with magnesium sulfate, filtered and concentrated under vacuum. The crude material was purified via silica gel chromatography using 20-60% Acetone in hexanes to give the desired product (2S,4R)-methyl 1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (10.8 g, 30% yield), MS: MS m/z 427.2 (M++1) and the undesired product (2S,4R)-methyl 1-((2R,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (12 g, 34% yield). MS: MS m/z 427.2 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][NH:40][C@@H:41]([CH3:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[N:40]([CH3:39])[C@H:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH3:48])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: CN[C@@H](C)c1ccccc1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N(C)[C@@H](C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 54 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (S)-N,α-dimethylbenzylamine: yield 54%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:18][CH2:19][C:20]2([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH2:12]OS(C)(=O)=O)[C:8]2[C:4](=[CH:5][N:6]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[N:7]=2)[CH:3]=1.[C-:48]#[N:49].[Na+].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:18][CH2:19][C:20]2([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:24][CH2:25]2)[CH2:12][C:48]#[N:49])[C:8]2[C:4](=[CH:5][N:6]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:46])[CH3:47])[N:7]=2)[CH:3]=1
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC(COC(COS(C)(=O)=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COC(CC#N)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 37.2 %

Procedure:
Tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-(methylsulfonyloxy)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (155 mg, 0.218 mmol) in DMF was added NaCN (21.37 mg, 0.436 mmol) and the reaction was stirred at R.T for 1 h. LC/MS showed no reaction. The reaction was heated at 50 C for another hour, LC/MS showed no reaction either. The reaction was again heated at 80 C for another hour, no reaction was observed. It was stirred at 80 C over the weekend. LC/MS showed product along with staring material. It was stirred at 80 C for 6 h, LC/MS showed the reaction was complete. The reaction was then partitioned between Et2O and H2O, the phase was separated and the aqueous phase was extracted with Et2O, the combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. It was purified by Biotage LC (30% EtOAc/Hex) to title compound (52.2 mg, 0.081 mmol, 37.3% yield). 1H-NMR (CDCl3, 300 MHz) δ 8.0 (s, 1H),), 7.53 (m, 1H), 7.32 (m, 2H), 7.05 (m, 2H), 6.63 (s, 1H), 5.61 (s, 2H), 5.04 (m, 1H), 3.68 (m, 2H), 3.57 (t, J=8.05 Hz, 2H), 3.45 (m, 2H), 3.05-2.96 (m, 3H), 2.74 (m, 1H), 2.28 (m, 1H), 1.98 (m, 1H), 1.96 (m, 1H), 1.83 (m, 1H), 1.42 (s, 9H), 0.9 (t, J=8.42 Hz, 2H); 13C-NMR (CDCl3, 126 MHz) δ 161.63 (d, J=245.7 Hz), 155.0, 144.8, 129.9, 128.9, 128.0, 124.0, 122.8, 119.3, 117.2, 115.5, 115.4, 81.9, 79.5, 79.0, 73.4, 67.8, 42.5, 41.4, 32.4, 28.6, 25.3, 17.9, 1.35. LC/MS (HPLC method 3): tR=4.16 min, 643.1 (MH)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[C:56]1([CH2:62][CH:63]=O)[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][N:53]([CH2:63][CH2:62][C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=5)[CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:39][CH:40]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Reactant: O=CCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C3(N4CCN(CCc5ccccc5)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 39.7 %

Procedure:
Using a procedure analogous to Example 15, the product from example 14 (100 mg, 0.125 mmol) was treated with phenylacetaldehyde (22.5 mg, 1.5 eq) to provide the title barbituric acid (45.0 mg, 40%). MS found: (M+H)+=564.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.[N:18]1([C:24]2[C:32]3[N:31]=[C:30]([C:33]([F:36])([F:35])[F:34])[NH:29][C:28]=3[CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[F:36][C:33]([F:34])([F:35])[C:30]1[NH:31][C:32]2[C:24]([N:18]3[CH2:19][CH2:20][N:21]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]4[N:9]=[C:10]5[C:5]([CH:4]=[CH:3][C:2](=[O:1])[NH:11]5)=[CH:6][CH:7]=4)[CH2:22][CH2:23]3)=[CH:25][CH:26]=[CH:27][C:28]=2[N:29]=1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: FC(F)(F)c1nc2c(N3CCNCC3)cccc2[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5nc(C(F)(F)F)[nH]c45)CC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
To a suspension of 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.211 g, 0.908 mmol, 1.29 eq) and 4-piperazin-1-yl-2-trifluoromethyl-1H-benzoimidazole (0.190 g, 0.703 mmol, 1 eq) in dichloroethane (5 mL) was added NaBH(OAc)3 (0.558 g, 2.631 mmol, 3.74 eq). The slurry was allowed to stir overnight at room temperature (18 h). The mixture was diluted with EtOAc and quenched with saturated NaHCO3. The organic phase was then washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. Purification by silica gel chromatography (2% MeOH/CH2Cl2) followed by formation of the HCl salt using 1N HCl in ether provided the title compound (0.230 g, 62%). MS: APCI: M+1: 487.1 (Exact Mass: 486.20).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][CH3:12])[CH:10]=1)[NH:7][C:6](=O)[C:5]2=O.[BH4-].[Li+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][CH3:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: CCc1cc(Br)cc2c1NC(=O)C2=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc(Br)cc2cc[nH]c12
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 5-bromo-7-ethyl-1H-indole-2,3-dione (36.0 g, 144 mmol) in tetrahydrofuran (120 mL) at room temperature was dropped a 2.0 M solution of lithium borohydride in tetrahydrofuran. The reaction mixture was stirred at 90° C. (oil bath) for 5 hours. After cooling down to room temperature, it was quenched with 5% hydrochloric acid solution until the excess lithium borohydride was destroyed. To the mixture was added saturated sodium bicarbonate solution (300 mL) and extracted with ethyl acetate. Extracts were dried over magnesium sulfate and concentrated under reduced pressure to give the crude product of 5-bromo-7-ethyl-1H-indole, which went to next reaction without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([CH2:11][NH:12][NH2:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:18][C:19](=O)[CH:20]=[C:21]([NH2:25])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:25][C:21]1[NH:13][N:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)[C:19](=[O:18])[CH:20]=1
Reactant: NNCc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(-c3ccccc3)cc2)[nH]1
Reaction time: 8 h

Procedure:
A solution of 29 g of 4-phenylbenzylhydrazine in 60 ml of ethanol was added dropwise, under nitrogen, to a solution of 23.4 g (0.147 mol) of β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid in 100 ml of ethanol. During addition the temperature rose from 22° to 32° C. After standing overnight, the reaction solution was concentrated in vacuo, the precipitate which separated out was dissolved in 2 N sodium hydroxide solution and the alkaline solution was repeatedly extracted with ether. Addition of dilute acetic acid until the mixture reacted weakly acid yielded the compound identified above, which melted at 185°-186° after recrystallisation from ethanol. 13 g (33%).