Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=1[NH2:6])([O-])=O.Cl[Sn]Cl.[OH-].[Na+]>C(O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]([NH2:1])=[C:5]([NH2:6])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(Cl)cc1N
Yield: 99.6 %

Procedure:
To 2-nitro-5-chloroaniline (304 mg, 1.76 mmol) in absolute ethanol (20 mL) was added SnCl2 (1.68g, 8.86 mmol) and refluxed overnight. The reaction mixture was then basified to pH 11 with 2N NaOH and extracted with ether to give 250 mg (quantitative yield) of product. This product was used without further purification for the synthesis of JSK IV-68.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:48][C:43]2[CH:44]=C[CH:46]=[N:47][C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN1CC(N)C1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:48][CH:43]5[CH2:42][N:47]([CH3:46])[CH2:44]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CC(N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylazetidin-3-amine hydrochloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58-1.71 (m, 7H) 1.90 (m, 3H) 2.42 (s, 3H) 3.32 (s, 3H) 3.76 (t, J=7.2 Hz, 2H) 3.94 (s, 3H) 4.05 (t, J=13.8 Hz, 2H) 4.38-4.60 (m, 1H) 4.76 (d, J=7.8 Hz, 1H) 7.35-7.59 (m, 2H) 7.99 (s, 1H) 8.26 (s, 1H) 8.29 (d, J=8.3 Hz, 1H) 8.72 (d, J=6.6 Hz, 1H). Melting point: 157-162° C. [M+H] calc'd for C25H31F2N7O3, 516. found 516.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenylamine (3.37 g, 9.24 mmol) in pyridine (30 ml) at 0° C. was charged with methanesulfonylchloride 1.3 ml, 16.5 mmol) dropwise, causing a color change from yellow to bright orange. The reaction was warmed to room temperature and judged complete by TLC after 3 h. The mixture was diluted with toluene and stripped twice. Following a water quench (20 ml), the product was extracted with EtOAc (4×30 ml), washed with saturated aqueous NaHCO3 solution (6×30 ml) and with saturated aqueous NaCl solution (3×30 ml), dried over Na2SO4, filtered and concentrated to a crude orange liquid. Flash chromatography on silica gel eluting with 2 to 5% MeOH/CH2Cl2 provided the title compound as orange oil (3.59 g, 85%). (TLC 5% MeOH/CH2Cl2 Rf 0.24); 1H NMR (400 MHz, CDCl3) δ 7.37–7.19 (m, 7H), 7.11 (br d, J=7.9 Hz, 1H), 7.05 (ddd, J=7.9, 2.1, 0.8 Hz, 1H), 3.73 (AB q, ΔAB 59.9, J=13.3 Hz, 2H), 3.71 (m, 1H), 3.09 (br, s, 1H), 3.04 (m, 1H), 2.94 (s, 3H), 2.80 (m, 1H), 2.18 (m, 2H), 2.07–1.95 (m, 4H), 1.82 (br d, J=12.0 Hz, 1H), 1.72 (m, 1H), 1.57 (m, 1H), 1.17 (m, 1H). 13C 154.2, 137.1, 132.3, 129.5, 129.4, 129.1, 128.6, 128.4, 127.1, 122.0, 118.3, 117.9, 60.1, 52.3, 49.4, 39.3, 38.9, 38.7, 37.4, 35.8, 24.9, 23.0; APCI MS m/z 385.1 (M+1)+.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:16]=[CH:15][S:14][N:13]=1)SC)#[N:2].[CH3:17][NH2:18]>>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:16]=[CH:15][S:14][N:13]=1)=[N:18][CH3:17])#[N:2]
Reactant: CN
Reactant: CSC(=NCCSCc1ccsn1)NC#N
Product: CN=C(NC#N)NCCSCc1ccsn1

Procedure:
The reaction of N-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-S-methylisothiourea (0.27 g.) with excess methylamine according to the procedure described in Example 3(c) and recrystallisation of the product from isopropyl acetate afforded N-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-N"-methylguanidine (0.12 g.), m.p. 91°-93°. (Found: C, 42.4; H, 5.1; N, 27.3; S, 25.2. C9H13N5S2 requires: C, 42.3; H, 5.1; N, 27.4; S, 25.1).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:15]=[CH:14][NH:13][N:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O-]CC.[Na+].CS(O[CH2:25][C@H:26]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:27])(=O)=O>C(#N)C>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:15]=[CH:14][N:13]([CH2:27][C@H:26]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH3:25])[N:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: Cc1c(-c2cc[nH]n2)ccc(C#N)c1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(-c2ccn(C[C@@H](C)NC(=O)OC(C)(C)C)n2)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 50.8 %

Procedure:
2-chloro-3-methyl-4-(1H-pyrazol-3-yl)benzonitrile (0.5 g, 2.297 mmol) was dissolved in dry acetonitrile (5 ml) under nitrogen and cooled to 0° C. Sodium ethoxide (0.313 g, 4.59 mmol) was added and the reaction mixture was stirred for 25 min and allowed to warm up to RT. (R)-2-(tert-butoxycarbonylamino)propyl methanesulfonate (0.582 g, 2.297 mmol) was dissolved in 5 ml of dry acetonitrile and added dropwise to the reaction mixture. The reaction mixture was refluxed for 15 h and then the solvents were evaporated. The residue was taken into EtOAc, washed several times with saturated aqueous NaHCO3 and water, dried with Na2SO4 and evaporated to dryness. CombiFlash purification afforded 0.437 g of the title compound using heptane/EtOAc-system as an eluent. 1H-NMR (400 MHz; d6-DMSO): δ 1.02 (d, 3H), 1.31 (s, 9H), 2.57 (s, 3H), 3.91 (m, 1H), 4.13 (m, 2H), 6.62 (m, 1H), 6.87 (d, 1H), 7.66 (d, 1H), 7.78 (d, 1H), 7.83 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([C:19]([NH:21][CH2:22][CH2:23][OH:24])=O)=[C:17]2[C:12]([C:13](=[O:36])[C:14]([CH3:35])=[C:15]([CH:25]3[CH2:30][CH2:29][N:28]([C:31](=[O:34])[CH2:32][CH3:33])[CH2:27][CH2:26]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.N12CCCN=C1CCCCC2.Cl>ClCCl.ClCCCl>[CH2:1]([O:8][C:9]1[C:18]([C:19]2[O:24][CH2:23][CH2:22][N:21]=2)=[C:17]2[C:12]([C:13](=[O:36])[C:14]([CH3:35])=[C:15]([CH:25]3[CH2:26][CH2:27][N:28]([C:31](=[O:34])[CH2:32][CH3:33])[CH2:29][CH2:30]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)N1CCC(c2oc3c(C(=O)NCCO)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCC(=O)N1CCC(c2oc3c(C4=NCCO4)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 27.8 %

Procedure:
To a solution of 7-(benzyloxy)-N-(2-hydroxyethyl)-3-methyl-4-oxo-2-(1-propanoylpiperidin-4-yl)-4H-chromene-8-carboxamide (140 mg, 0.28 mmol) obtained in Example 35-2 in dichloromethane (4 mL), thionyl chloride (62 μL, 0.85 mmol) was added dropwise, and then the mixture was stirred at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure, and then the residue was subjected to azeotropy with toluene (6 mL). 1,2-Dichloroethane (4 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (950 μL, 5.68 mmol) were added to the obtained residue, and then the mixture was heated to reflux for 4 days. A 0.2 N aqueous hydrochloric acid solution (50 mL) was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-hexane/ethyl acetate=90/10→60/40) to obtain 37 mg of the title compound (yield: 27%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12]([C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: Nc1cccc2cccnc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(Nc2cccc3cccnc23)cc1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condensor, and nitrogen inlet was added 8-aminoquinoline (14.4 grams, 0.10 moles), 4-tert-butyl bromobenzene (21.3 grams, 0.10 moles), tris(dibenzylideneacetone)dipalladium (0) (1.8 grams, 0.002 moles), rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (2.5 grams, 0.004 moles), sodium tert-butoxide (19.4 grams, 0.20 moles) and anhydrous toluene (150 mL). The contents of the flask were refluxed for four days; cooled to room temperature; and filtered through a pad of silica gel. The silica gel pad was then eluted with dichloromethane (240 mL). The combined organic layers were concentrated in vacuo to yield a dark blue solid. The solid was chromatographed on silica gel, eluting with hexane/ethyl acetate (20:1) to afford 23 grams of the desired product as a yellow solid. 1H NMR (CDCl3) □ 8.8 (m, 1H), 8.2 (bs, 1H), 8.1 (d, 1H), 7.1-7.5 (m, 9H), 1.35 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:20]([F:23])([F:22])[F:21])[N:4]=1.I([O-])(=O)(=O)=[O:25].[Na+].CN(C=O)C>CCOC(C)=O>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[C:3]([CH:2]=[O:25])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:20]([F:23])([F:22])[F:21])[CH:8]=[CH:7][CH:6]=2
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: FC(F)(F)c1cccc2nc(CBr)c(-c3ccccc3Cl)nc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1nc2cccc(C(F)(F)F)c2nc1-c1ccccc1Cl
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(bromomethyl)-3-(2-chlorophenyl)-5-(trifluoromethyl)quinoxaline (0.5137 g, 1.279 mmol) and sodium metaperiodate (0.1416 mL, 2.558 mmol) in DMF (8.527 mL, 1.279 mmol) was heated at 150° C. with stirring. After 3 h, the mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 10% gradient of EtOAc in hexane over 10 min, then 10% isocratic of EtOAc for 20 min, then 10 to 40% gradient of EtOAc in hexane over 20 min, then 40% isocratic of EtOAc for 5 min as eluent to give 3-(2-chlorophenyl)-5-(trifluoromethyl)quinoxaline-2-carbaldehyde as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.15 (1 H, s), 8.66 (1 H, dd, J=8.6, 1.2 Hz), 8.52 (1 H, d, J=7.0 Hz), 8.18 (1 H, t, J=8.0 Hz), 7.53-7.67 (4 H, m); LC-MS (ESI) m/z 337.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[NH:5][CH:6]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([N:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:22][CH2:21]2)=[O:9])[NH:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)c[nH]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Br)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a mixture of 4-bromo-1H-pyrrole-2-carboxylic acid (800 mg, 4.21 mmol), tert-butylpiperazine-1-carboxylate (822 mg, 4.42 mmol), BOP (2.2 g, 5.05 mmol) in DMF (5 mL), DIEA (1.63 g, 12.63 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to afford the crude product (920 mg, 61% yield) which was used directly in the next step without purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:16]([CH3:24])([CH2:17][CH2:18][C:19]=32)[C@@H:11]([C@H:12]([CH3:15])[CH:13]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:26])[CH3:25].[N:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[N:33]1[CH2:38][CH2:37][N:36]([CH2:15][C@H:12]([C@@H:11]2[C@:16]3([CH3:24])[C:8]([C:7]4[CH2:6][CH2:5][C@@H:4]5[C@:20]([C:19]=4[CH2:18][CH2:17]3)([CH3:23])[CH2:21][CH2:22][C@H:2]([OH:1])[C:3]5([CH3:26])[CH3:25])=[CH:9][CH2:10]2)[CH3:13])[CH2:35][CH2:34]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: C[C@H](C=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@H](CN1CCN(c2ncccn2)CC1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-al was treated with N-(pyrimidin-2-yl)piperazine and sodium tris(acetoxy)borohydride as described in Example 1h). (20S)-20-[(4-(pyrimidin-2-yl)piperazin-1-yl)methyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH:18]=O.[CH2:20]([NH:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][N:22]([CH2:20][CH3:21])[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCC=O
Reactant: CCNc1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCN(CC)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 531A (130 mg) and N-ethylnaphthalen-1-amine (82 mg) in dichloromethane (3 mL) was added sodium triacetoxyborohydride (2.35 g). The mixture was stirred at room temperature overnight. After this time the mixture was diluted with ethyl acetate (1500 mL) and washed with 1N NaOH, water, brine, and dried over Na2SO4. After filtration and concentration of the filtrate, the residue was purified by flash chromatography using silica gel and eluenting with 5% ethyl acetate in hexane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:13])[C:9](C)([CH3:11])[CH3:10])[CH:2]=1.CN(C)CCN(C)C.C([Li])CCC.[I:27]I>O1CCCC1.CCCCCC>[CH3:10][CH:9]([CH3:11])[C:8]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][C:4]=1[I:27])=[O:13]
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1cccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)C(=O)Nc1cnccc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
A solution of 91 g (510 mmol) N-3-pyridylpivalamide and 230 ml (1.53 mol) N,N,N′,N′-tetramethylethylenediamine under argon in 2000 ml tetrahydrofuran was cooled in a dry ice bath to −78° C. Within 1 h, 153 ml (1.53 mmol) of a 10 N n-butyllithium solution in hexane were added dropwise. The reaction mixture was stirred at 0° C. for additional 2 h. After cooling again to −78° C., 380 g (1.5 mol) iodine dissolved in 300 ml tetrahydrofuran were added dropwise during 1.5 h. The dry ice bath was removed and the reaction mixture was allowed to warm up to room temperature overnight. Stirring was continued and 1000 ml water and 1000 ml saturated sodium thiosulfate pentahydrate solution were added. The aqueous layer was separated and extracted twice with 800 ml ethyl acetate. The combined organic layers were dried (magnesium sulfate) and evaporated. Chromatographical filtration gave 75 g (48%) of the title compound as brown crystals.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=3)[N:7]=[C:6]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:5]=2[C:26](O)=[O:27])[CH2:3][CH2:2]1.Cl.Cl.[NH:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:41][CH2:40][CH2:39][C@H:38]2[CH2:42][OH:43])[CH2:33][CH2:32]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:18])([F:19])[F:17])[CH:10]=3)[N:7]=[C:6]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)[C:5]=2[C:26]([N:31]2[CH2:32][CH2:33][CH:34]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[CH2:42][OH:43])[CH2:35][CH2:36]2)=[O:27])[CH2:3][CH2:2]1
Reactant: O=C(O)c1c(-c2ccncc2)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1
Reactant: OC[C@@H]1CCCN1C1CCNCC1
Agent: Cl
Product: O=C(c1c(-c2ccncc2)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1)N1CCC(N2CCC[C@H]2CO)CC1
Yield: 56 %

Procedure:
In analogy to the procedure described in Example 160E, 5-cyclopropyl-3-pyridin-4-yl-1-(3-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid (Example 162D]) and ((S)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanol dihydrochloride (Example 161A]) gave the title compound as a light brown oil (56%). MS: 556.2 (MH+).
Reaction SMILES: [OH:1][C:2]([C:17]([F:20])([F:19])[F:18])([CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])([CH3:8])[CH3:7])[CH:3]=O.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[NH2:31]>C1(C)C=CC=CC=1.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[F:20][C:17]([F:18])([F:19])[C:2]([CH:3]=[N:31][C:22]1[CH:23]=[CH:24][C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=1)([OH:1])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])([CH3:7])[CH3:8]
Reactant: COc1ccccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1ccc2ccccc2c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccccc1C(C)(C)CC(O)(C=Nc1ccc2ccccc2c1)C(F)(F)F
Yield: 89.8 %

Procedure:
150 mg (0.517 mmol) of 2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal is converted into imine with 74 mg (0.517 mmol) of 2-naphthylamine in toluene with the aid of titanium tetraisopropylate. After working-up and chromatography, 192.8 mg (89.8%) of the desired imine is isolated.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])=[C:10]([OH:23])[N:9]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:25]3)[C:8]2=[O:40])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:10]([OH:23])[N:9]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[O:31])[CH2:25]3)[C:8]2=[O:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCN(C(=O)OCc3ccccc3)C2)c(=O)n(C2CCCCC2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCN(C(=O)OCc3ccccc3)C2)c(=O)n(C2CCCCC2)c1=O
Reaction time: 2 h

Procedure:
Phenylmethyl 3-[3-cyclohexyl-5-({[2-(ethyloxy)-2-oxoethyl]amino}carbonyl)-6-hydroxy-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-1-piperidinecarboxylate (100 mg, 0.18 mmoles) was dissolved in ethanol (3.0 mL) and treated with 6 molar sodium hydroxide (1.5 mL). The mixture was stirred for 2 hours, acidified and extracted with ethyl acetate (×2). The combined extracts were washed with 1 molar hydrochloric acid, dried and evaporated to a foam (80 mg, 84%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (s, 1 H), 10.17 (s, 1 H), 7.30-7.40 (m, 5 H), 5.10 (s, 2H), 4.57-4.69 (m, 2 H), 4.13 (d, J=5.81 Hz, 2 H), 3.95-4.05 (m, 2 H), 3.64 (s, 1 H), 3.37 (s, 1 H), 2.73 (s, 1 H), 2.36-2.48 (m, 1 H), 2.25 (q, J=11.62 Hz, 2 H), 1.70-1.82 (m, 4 H), 1.62 (d, J=11.37 Hz, 3 H), 1.38-1.50 (m, 1 H), 1.21-1.33 (m, 2 H), 1.06-1.18 (m, 1 H)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:17]([CH3:42])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH2:40][CH3:41])[N:19]=3)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:40]([C:32]1[N:31]([C:20]2[N:19]=[C:18]3[C:23]([N:24]=[C:16]([C:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[O:15])[N:17]3[CH3:42])=[C:22]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:21]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1)[CH3:41]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)C3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)C3CCNCC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbonyl]piperidine-1-carboxylic acid tert-butyl ester (58 mg, 0.10 mmol) in DCM (1 mL) was added TFA (1 mL) and the resulting mixture stirred at r.t. for 1 h. The reaction mixture was concentrated in vacuo and azeotroped with DCM affording [2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-4-ylmethanone. LCMS (method A): RT 2.03 min, [M+H]+ 475.3
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:15]=[C:16](Br)[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O.CN(C)C=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[C:16]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[C:27]([F:38])([F:37])[F:26])[CH:15]=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc(Br)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(-c3ccccc3C(F)(F)F)c2)cc1

Procedure:
In a 5 mL microwave vial, 5-Bromo-4′-methyl-biphenyl-3-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide (30.00 mg, 0.07589 mmol), 2-(trifluoromethyl)phenylboronic acid (28.83 mg, 0.1518 mmol), cesium carbonate (123.6 mg, 0.3795 mmol), tetra-n-butylammonium iodide (28.03 mg, 0.07589 mmol), and POPd (3.808 mg, 0.007589 mmol) were dissolved in Water (0.06 mL, 3 mmol) and N,N-dimethylformamide (0.3 mL, 4 mmol). The reaction mixture was microwaved for 20 mins at 150 degrees. The reaction was purified directly by reversed phase chromatography.