Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]=2[S:8][C:7]=1[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.Cl[C:34]([O:36][CH3:37])=[O:35]>>[CH3:16][N:12]1[C:13](=[O:15])[C:14]2[C:6]([S:5][CH2:4][CH2:3][CH2:2][NH:1][C:34](=[O:35])[O:36][CH3:37])=[C:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[S:8][C:9]=2[N:10]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:11]1=[O:17]
Reactant: COC(=O)Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCN)c(Cc3cccc4ccccc34)sc21
Product: COC(=O)NCCCSc1c(Cc2cccc3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Yield: 35.6 %

Procedure:
Prepared from 5-[(3-aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 mg) and methyl chloroformate (34 mg) following the method of Example 41 to give the title compound (4 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.C(O)C.C(#N)C.C([O-])(=O)C.[Ca+2:43].C([O-])(=O)C>C1CCCCC1.O>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[Ca:43]
Reactant: [Ca+2]
Agent: CC(=O)[O-]
Agent: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Solvent: CCO
Solvent: C1CCCCC1
Solvent: O
Product: [Ca]
Temperature: 67.5 °C
Reaction time: 5 h

Procedure:
Raltegravir (10 gm), ethanol (60 ml), acetonitrile (40 ml), water (2 ml) and calcium acetate (4 gm) were added at 25 to 30° C. The contents were heated to 65 to 70° C. and distilled off solvent completely under vacuum at 45° C. to obtain residue. To the residue was added cyclohexane (50 ml) and again distilled to obtain residue. Cyclohexane (100 ml) was added to the residue and stirred for 5 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 10 gm of raltegravir calcium.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][C:16]=1[NH:24][C:25](=[O:41])[CH2:26][CH:27]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH3:14])([CH3:13])[CH3:12].[C:42](N1C=CN=C1)(=[O:44])[CH3:43]>C1(C)C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH:22][C:42](=[O:44])[CH3:43])=[CH:17][C:16]=1[NH:24][C:25](=[O:41])[CH2:26][CH:27]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(=O)n1ccnc1
Reactant: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccccc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCC(CC(=O)Nc1cc(C(=O)NC(C)=O)ccc1C(C)(C)C)c1ccccc1OC
Reaction time: 0.25 h

Procedure:
2.39 ml (1.19 mmol) of a 0.5 M potassium bis(trimethylsilyl)amide solution in toluene were added dropwise at room temperature over a period of 3 minutes to a solution of 338 mg (0.78 mmol) of N-(2-t-butyl-5-carbamoylphenyl)-3-(2-methoxyphenyl)octanamide (prepared as described in Example 151) in 5.0 ml of dry tetrahydrofuran, and the resulting mixture was stirred for 15 minutes, after which 175 mg (1.59 mmol) of 1-acetylimidazole were added. The reaction mixture was stirred for 40 minutes, after which it was diluted with ethyl acetate, and the diluted solution was washed with a saturated aqueous solution of potassium hydrogensulfate and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 363 mg (a quantitative yield) of the title compound as a colorless foam-like substance.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C1(N)C=CC=CC=1N.C(OC(N1CC(C(O)=O)C1)=O)(C)(C)C.C(N(CC)CC)C.[NH2:54][C:55]1[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][C:56]=1[NH:62][C:63]([CH:65]1[CH2:68][N:67]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:66]1)=O>CN(C=O)C.C(O)(=O)C.O>[Cl:61][C:58]1[CH:59]=[CH:60][C:55]2[NH:54][C:63]([CH:65]3[CH2:68][N:67]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:66]3)=[N:62][C:56]=2[CH:57]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)Nc2cc(Cl)ccc2N)C1
Agent: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(c2nc3cc(Cl)ccc3[nH]2)C1
Reaction time: 16 h
Yield: 94.2 %

Procedure:
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2926 mg, 7.71 mmol) was added to a solution of o-phenylenediamine, 4-chloro- (1000 mg, 7.01 mmol), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (1411 mg, 7.01 mmol), and triethylamine (1.075 mL, 7.71 mmol) in DMF (30 mL) under argon at 0° C. The mixture was stirred for 16 h with warming to RT before water (100 mL) was slowly added, at which time a suspension formed. The mixture was filtered and the collected solid was washed with water several times and then air-dried. The solid was dissolved in EtOAc and the mixture was washed with satd. NaHCO3, brine, dried (MgSO4), decolorized with activated charcoal, filtered, and concentrated in vacuo to give product as an off-white solid as a 4:1 ratio of regioisomers. A solution of tert-butyl 3-(2-amino-5-chlorophenylcarbamoyl)azetidine-1-carboxylate (2.28 g, 7.00 mmol) in acetic acid (20 mL) was heated to 100° C. for 1 h. The acetic acid was removed in vacuo and the resulting solid was partitioned between EtOAc and saturated NaHCO3. The layers were separated and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo to give tert-butyl 3-(5-chloro-1H-benzo[d]imidazol-2-yl)azetidine-1-carboxylate as a light brown solid (2.03 g, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:24]([F:27])([F:26])[F:25])=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)(=[O:12])=[O:11])([O-])=O.Cl[Sn]Cl>Cl.CCO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:24]([F:27])([F:26])[F:25])=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccc(C(F)(F)F)c2cccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccccc1S(=O)(=O)Nc1ccc(C(F)(F)F)c2cccnc12
Yield: 90.7 %

Procedure:
In a similar fashion using route 1 general procedure 4, 2-nitro-N-(5-trifluoromethyl-quinolin-8-yl)-benzenesulfonamide (Intermediate 253) (275 mg, 0.69 mmol), SnCl2 (526 mg, 3.46 mmol), conc.HCl (5 drops) and EtOH (10 ml) gave the title compound (230 mg, 90%) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:23]([O-])=O)=[C:6]([CH:22]=1)[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=1[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2cc(Cl)ccc2[N+](=O)[O-])sc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2cc(Cl)ccc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(5-chloro-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-5-chloroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH:16]([C:18]1[CH:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=1)=[CH2:17].[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:17][CH2:16][C:18]3[CH:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(=O)[nH]c1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccc(=O)[nH]c2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([O:10][Si](C(C)C)(C(C)C)C(C)C)[C:7]([CH3:21])=[CH:6][C:3]=1[CH:4]=O.Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH:31]([CH3:33])[CH3:32])[C:24]=1[CH3:34]>>[CH3:21][C:7]1[CH:6]=[C:3]([CH2:4][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH:31]([CH3:32])[CH3:33])[C:24]=2[CH3:34])[C:2]([CH3:1])=[CH:9][C:8]=1[OH:10]
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(C)cc1C=O
Reactant: COc1ccc(Br)c(C)c1C(C)C
Product: COc1ccc(Cc2cc(C)c(O)cc2C)c(C)c1C(C)C

Procedure:
Intermediate 2,5-dimethyl-4-(4′-methoxy-2′-methyl-3′-iso-propylbenzyl)phenol was prepared from 2,5-dimethyl-4-triisopropylsilanyloxy-benzaldehyde and 1-bromo-4-methoxy-2-methyl-3-iso-propylbenzene according to the procedure described in G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607 and transformed into the title compound by the procedure described for the synthesis of compound 7: 1H NMR (300 MHz, DMSO-d6): δ6.93 (s, 1 H), 6.75 (d, J=8.4 Hz, 1 H), 6.65 (d, J=8.4 Hz, 1 H), 6.64 (s, 1 H), 4.09 (d, J=9.9 Hz, 2 H), 3.79 (s, 2 H), 3.77 (s, 3 H), 3.34 (m, 1 H), 2.22 (s, 3 H), 2.20 (s, 3 H), 2.10 (s, 3 H), 1.31 (d, J=7.2 Hz, 6 H); LC-MS m/z=391 [C21H29O5P−H]−.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)([F:4])[CH3:3].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[F:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([F:4])[CH3:3]
Reactant: C1CNCCN1
Reactant: CC(F)(F)c1ccccc1Br
Product: CC(F)(F)c1ccccc1N1CCNCC1

Procedure:
A solution of diethylaminosulfur trifluoride (560 mg, 3.47 mmol, 3 eq) and 2-bromoacetophenone (230 mg, 1.16 mmol, 1.0 eq) was heated to 40° C. for about 72 hours. The solution was diluted with CH2Cl2 and washed with saturated sodium bicarbonate, water, brine, dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography (35 g SiO2, linear gradient 0-10% ethyl acetate/Hexanes, 30 mL/minute, over 30 minutes) afforded about 125 mg (0.57 mmol, 49%) of 2-(1,1-difluoroethyl)-1-bromobenzene. GC/MS (EI): 220 (M+H). 2-(1,1-Difluoroethyl)-1-bromobenzene was coupled to piperazine in a manner similar to Preparation 1A. LRMS (ESI+): 227.2 (M+1)
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[C:11]([CH2:19][CH2:20][NH:21][CH3:22])=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](O)(C(F)(F)F)=O.C=O>C(#N)C>[CH:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[C:11]3[CH2:19][CH2:20][N:21]([CH3:23])[CH2:22][C:10]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: CNCCc1cn(CCC2CCCCC2)c2ccc(C)cc12
Agent: C=O
Solvent: CC#N
Product: Cc1ccc2c(c1)c1c(n2CCC2CCCCC2)CN(C)CC1
Temperature: 25 °C

Procedure:
2-(1-(2-cyclohexylethyl)-5-methyl-1H-indol-3-yl)-N-methylethanamine (72 mg, 0.23 mmol) was dissolved in acetonitrile (2 mL) containing 5% TFA and the reaction mixture was refluxed. 37% aqueous formaldehyde (0.02 mL) was added to the reaction mixture and refluxed for additional 2 h, cooled to 25° C., concentrated under reduced pressure and partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by silica gel chromatography (eluent EtOAc/EtOH/NH3: 9/1/0.1) to obtain 9-(2-cyclohexylethyl)-2,3,4,9-tetrahydro-2,6-dimethyl-1H-pyrido[3,4-b]indole (52 mg). The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF. 1H NMR (DMSO): 7.5 (d, 1H), 7.4 (s, 1H), 6.9 (d, 1H), 4.3 (bs, 2H), 4.0 (t, 2H), 3.6 (bs, 2H), 2.8 (m, 5H), 2.3 (s, 3H), 1.8-0.7 (m, 13H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH2:21]([NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:21]([N:28]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)NCc1ccccc1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)N(Cc1ccccc1)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with N-benzyl-2-methylpropan-2-amine (CAN 3378-72-1) in the presence of TBTU and DIEA to obtain the title compound as colorless solid; MS (EI): m/e=430.5 [MH+].
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([N:12]=[C:13]([C:15]4[C:32]([F:33])=[CH:31][C:18]([O:19][CH2:20][C@@H:21]([NH:23]C(=O)OC(C)(C)C)[CH3:22])=[CH:17][C:16]=4[F:34])[CH:14]=3)[CH:11]=2)[CH2:3][CH2:2]1.[C:35](OCC)(=[O:37])[CH3:36].Cl>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([N:12]=[C:13]([C:15]4[C:16]([F:34])=[CH:17][C:18]([O:19][CH2:20][C@@H:21]([NH:23][C:35](=[O:37])[CH3:36])[CH3:22])=[CH:31][C:32]=4[F:33])[CH:14]=3)[CH:11]=2)[CH2:2][CH2:3]1
Reactant: C[C@@H](COc1cc(F)c(-c2cc3ccc(OCC4CC4)cn3n2)c(F)c1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cc(F)c(-c2cc3ccc(OCC4CC4)cn3n2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl [(1S)-2-{4-[6-(cyclopropylmethoxy)pyrazolo[1,5-a]pyridin-2-yl]-3,5-difluorophenoxy}-1-methylethyl]carbamate (130 mg) and 4 M hydrogen chloride-ethyl acetate (2 mL) was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure. To the residue were added pyridine (2 mL) and acetic anhydride (0.26 mL). The mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to afford the title compound (40 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[I-].[K+].Br[CH2:16][CH2:17][CH2:18][OH:19]>C(O)C.O>[OH:19][CH2:18][CH2:17][CH2:16][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(OCCCO)cc1
Reaction time: 24 h
Yield: 75.6 %

Procedure:
To a solution of 4-hydroxybenzoic acid (25.0 g, 0.18 mol), potassium hydroxide (27.6 g, 0.49 mol), and potassium iodide (3.0 g, 0.018 mol) in ethanol (75 mL) and water (5 mL) was added dropwise 3-bromopropanol (25.6 g, 0.19 mol). The reaction was allowed to continue for 24 h under reflux. The solid residue was filtered off, and the filtrate was evaporated to dryness. The resultant solid was dissolved in water (200 mL) and then acidified with a 10% HCl solution. The precipitate was filtered for recrystallization from ethanol: water (1:1) to yield 1(26.7 g, 75%). 1H NMR (200 MHz, DMSO-d6): δ 1.85 (quintet, 2H, —CH2—), δ 3.55 (t, 2H, —CH2OAr), δ 4.10 (t, 2H, HOCH2—), δ 6.95 (d, 2H, aromatic ring), δ 7.85 (d, 2H, aromatic ring).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][C:6]=2[N:20]=1.[H-].[Na+].[C:31]([N:35]=[C:36]=[O:37])([CH3:34])([CH3:33])[CH3:32].C>CN(C=O)C.O>[C:31]([NH:35][C:36]([NH:1][C:2]1[C:3]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][C:6]=2[N:20]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)N=C=O
Reactant: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)NC(C)(C)C)nc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
To a solution of 7-amino-6-(2,6-dichlorophenyl)-2-(3-diethylamino-propylamino)-pyrido[2,3-d]pyrimidine (0.48 g) from Example 20 in DMF (5 mL) was added 60% sodium hydride suspension (46 mg), and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added t-butyl isocyanate (0.113 g), and the mixture was stirred for 18 hours. The reaction mixture was diluted with water and the insoluble material was collected by filtration. The solid was suspended in water (20 mL) and acidified with 1.0N HCl to form a solution. Activated charcoal was added to the solution, and the suspension filtered through celite, washing with water. The filtrate was made basic with 1.0N NaOH, and the insoluble product was collected by filtration and washed with water. A 180-mg sample of the product was further purified by reverse phase preparative HPLC on a C18 reverse phase column, eluting with a solvent gradient starting from 86% of 0.1% trifluoroacetic acid in water/14% acetonitrile to 14% of 0.1% trifluoroacetic acid in water/86% acetonitrile over a 22-minute time period to afford 165 mg of 1-tert-butyl-3-[6-(2,6-dichlorophenyl)-2-(3-diethylamino-propylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea, mp dec >80° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1>S([O-])([O-])(=O)=O.[Ba+2].[Pd+2].S([O-])([O-])(=O)=O.C(O)(=O)C>[CH3:2][C:3]1[NH:4][C:5]2[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: COC(=O)c1ccc2nc(C)[nH]c2c1
Agent: [Pd+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Product: COC(=O)C1CCc2nc(C)[nH]c2C1
Reaction time: 115 h
Yield: 12 %

Procedure:
In an autoclave 6.8 g (30 mmols) of methyl 2-methylbenzimidazole-5-carboxylate hydrochloride, 6.0 g of 5% palladium-barium sulfate and 140 ml of acetic acid were charged and hydrogenation was carried out at 80° C. for 115 hours under 60 atms with stirring. After cooling, 5% palladium-barium sulfate was filtered off and the filtrate was distilled off under reduced pressure. After 200 ml of water was added to the residue, 1 N sodium hydroxide solution was added to the mixture at 0° to 5° C. to adjust pH to 9 to 10 followed by extraction with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with methylene chloride-methanol (10 : 1) to give 0.70 g (12.0%) of methyl 2-methyl-4,5,6,7-tetrahydrobenzimidazole-5-carboxylate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH:12]2[O:13][CH2:14][CH:15]([OH:16])[CH:11]2[O:10][CH2:9]1>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH:12]2[O:13][CH2:14][C:15](=[O:16])[CH:11]2[O:10][CH2:9]1
Reactant: OC1COC2C(OC3CCCCO3)COC12
Solvent: ClCCl
Product: O=C1COC2C(OC3CCCCO3)COC12
Temperature: 30 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 6-((tetrahydro-2H-pyran-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (5.0 g, 21.7 mmol) in DCM (150 mL) was added DMP (18.4 g, 43.5 mmol) at rt, and then the mixture was stirred at 30° C. overnight and concentrated in vacuo. The residue was dissolved in water (150 mL), and extracted with EtOAc (150 mL×3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as yellow oil (4.96 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.[Se](=O)=[O:28]>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[O:28])[O:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1cc(=O)c(-c2ccc(F)cc2F)c(-c2ccc(S(C)(=O)=O)cc2)o1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2oc(C=O)cc(=O)c2-c2ccc(F)cc2F)cc1
Temperature: 180 °C
Yield: 48.4 %

Procedure:
To a solution of 3-(2,4-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one (1.7 g; 4.5 mmoles) (compound 13) in dioxane (45 ml), selenium dioxide (2.2 g, 20 mmoles) was added and the mixture heated in a pressure vessel at 180° C. for 1 hour. After cooling, the reaction mixture was filtered, the solvent removed under reduced pressure and the residual oil purified by column chromatography with silica gel and ethyl acetate as eluent. 5-(2,4difluorophenyl)-6-(4-methanesulfonylphenyl)-4-oxo-4H-pyran-2-carbaldehyde (0.85 g) was obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=O.[CH2:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C.[OH-].[K+]>>[CH2:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[O:1][CH2:5][CH2:4][NH2:3])[CH2:8][CH2:7][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCc1ccccc1O
Reactant: O=C1NCCO1
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCc1ccccc1OCCN

Procedure:
To a 250 mL round bottom flask equipped with a thermocouple, heating mantle, nitrogen inlet/outlet, a condenser and a stir bar was added 2-oxazolidinone (6.72 g, 77.2 mmole), 2-nonylphenol (10.0 g, 45.4 mmole), potassium hydroxide (255 mg, 4.5 mmole) and ExxonMobil™ Aromatic 100 solvent (70 mL). The resulting mixture was heated to reflux temperature for 3 h. Reaction progress was monitored by TLC and 1H NMR. The reaction mixture was then cooled, filtered over Celite® and the solvent were evaporated under reduced pressure. The crude material was purified using flash column chromatography to give the amine. 1H NMR (DMSO-d6, 400 MHz) δ 7.26-7.12 (m, 2H), 6.88-6.81 (m, 2H), 3.87 (dd. 2H, J=5.8, 5.8 Hz), 2.86 (dd, 2H, J=5.8, 5.8 Hz), 1.75-0.42 (m, 19H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:8])[C:5]#[C:6][CH3:7].[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:9][C:10]1[CH:15]=[C:14]([O:8][CH:4]([CH3:3])[C:5]#[C:6][CH3:7])[N:13]=[CH:12][N:11]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC#CC(C)O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CC(C)Oc1cc(Cl)ncn1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
In 1 ml of tetrahydrofuran was suspended 0.04 g of sodium hydride (60% in oil), to which 0.5 ml of a tetrahydrofuran solution containing 0.06 g of 3-pentyn-2-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes and then cooled to 0° C., to which 0.5 ml of a tetrahydrofuran solution containing 0.1 g of 4,6-dichloropyrimidine was slowly added dropwise, followed by further stirring for 30 minutes. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with t-butyl methyl ether. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.12 g of 4-chloro-6-(1-methyl-2-butynyloxy)pyrimidine.