Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[CH:6]=[CH:7]/[CH2:8]P(OCC)(OCC)=O)=[O:5].C([Li])CCC.[C:22]([O:25][C@@H:26]1[CH2:48][CH2:47][C@@:46]2([CH3:49])[CH:28]([CH2:29][CH2:30][C@@H:31]3[C@@H:45]2[CH2:44][C@H:43]([O:50][C:51](=[O:53])[CH3:52])[C@@:42]2([CH3:54])[C@H:32]3[CH2:33][CH2:34][C@@H:35]2[C@H:36]([CH3:41])[CH2:37][CH2:38][CH:39]=O)[CH2:27]1)(=[O:24])[CH3:23].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>C(COC)OC.CCCCCC>[CH2:2]([O:3][C:4](=[O:5])/[CH:6]=[CH:7]/[CH:8]=[CH:39]/[CH2:38][CH2:37][CH:36]([C@@H:35]1[C@:42]2([CH3:54])[C@H:32]([C@H:31]3[C@H:45]([CH2:44][C@@H:43]2[O:50][C:51](=[O:53])[CH3:52])[C@:46]2([CH3:49])[C@@H:28]([CH2:27][C@H:26]([O:25][C:22](=[O:24])[CH3:23])[CH2:48][CH2:47]2)[CH2:29][CH2:30]3)[CH2:33][CH2:34]1)[CH3:41])[CH3:1]
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)C(CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC=O)[C@@]4(C)[C@@H](OC(C)=O)C[C@@H]32)C1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Product: CCOC(=O)/C=C/C=C/CCC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C[C@H](OC(C)=O)[C@]12C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 19.6 g of freshly distilled triethyl 4-phosphonocrotonate in 50 ml of dry glyme was added (at -70° ) 50 ml of a 1.6 M solution of butyl lithium in hexane. After 15 min the temperature was brought to -10° and 30 g of 3α,12α-diacetoxycholan-24-al was dissolved in 200 ml of dry glyme was added dropwise. After stirring for 20 min at this temperature the reaction mixture was allowed to warm to room temperature and stirred for 0.5 hr. The reaction mixture was then poured into 2 liters of a 5% monobasic sodium phosphate solution and the mixture extracted with ether. The ether solution was washed with a saturated aqueous sodium chloride solution and dried (MgSO4). The solvent was removed under reduced pressure and the residue after being dissolved in a minimum amount of benzene was washed through 300 g of silica gel. The column was eluted with 4 liters of benzene and then 4 liters of 0.5% ethyl acetate-benzene solution, and the solids obtained therefrom were combined to give 20.7 g of crude 7-(3α,12α-diacetoxy-5β-pregnane-20-yl)-trans,trans- 2,4-heptadienoic acid ethyl ester. Trituration with petroleum ether afforded 13.1 g of 7-(3α,12α-diacetoxy-5β-pregnane-20-yl)-trans,trans-2,4-heptadienoic acid ethyl ester, mp 129°-131°, plus a second crop of 2.4 g, mp 128°-130°. Crystallization from methanol afforded the analytical sample, mp 130°-132°.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[CH2:10]([NH2:12])[CH3:11]>>[CH2:10]([NH:12][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])=[O:9])[CH3:11]
Reactant: CCN
Reactant: Cc1ccsc1C(=O)O
Product: CCNC(=O)c1sccc1C
Yield: 92 %

Procedure:
Following the procedure as described in Preparation 18, making variations only as required to use 3-methylthiophene-2-carboxylic acid in place of 3-methylfuran-2-carboxylic acid to react with ethylamine in place of benzylamine, N-ethyl-3-methylthiophene-2-carboxamide was obtained as a colorless liquid in 92% yield: 1H NMR (300 MHz, CDCl3) δ 7.24 (d, J=5.0 Hz, 1H), 6.88 (d, J=5.0 Hz, 1H), 5.77 (br s, 1H), 3.51-3.40 (m, 2H), 2.51 (s, 3H), 1.24 (t, J=7.3 Hz, 3H); MS (ES+) m/z 170.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.S1(=O)(=O)CCCC1.C([N:32]([C:38]([O-])=[O:39])[N:33]=[CH:34]N(C)C)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:22]2[CH:34]=[N:33][NH:32][C:38]2=[O:39])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: CCN(N=CN(C)C)C(=O)[O-]
Reactant: COc1ccc(N2CCN(c3ccc(N)cc3Br)CC2)cc1
Solvent: CCO
Solvent: O=S1(=O)CCCC1
Product: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3Br)CC2)cc1
Temperature: 25 °C

Procedure:
To a stirred mixture of 54.3 parts of 3-bromo-4-[4-(4-methoxyphenyl)-1-piperazinyl]-benzenamine and 189 parts of tetrahydrothiophene 1,1-dioxide was added portionwise, during a 30 minutes-period, 28.6 parts of ethyl[(dimethylamino)methylene]hydrazinecarboxylate at 160° C. Upon completion, stirring and heating were continued at 170° C. till all ethanol was distilled off. After cooling to room temperature, 120 parts of 4-methyl-2-pentanone were added to dissolve the sticky residue. The whole was heated till a solution was obtained. After cooling, the supernatant phase was decanted and the residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 44.6 parts of 4-[3-bromo-4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (int. 34).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:3]=1.C[O:27][B:28](OC)[O:29]C>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:7]1[C:6]2[CH:5]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:3]=[C:2]([B:28]([OH:29])[OH:27])[C:10]=2[N:9]=[C:8]1[CH3:11]
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1ccccc1Cl
Reactant: COB(OC)OC
Product: Cc1nc2c(B(O)O)cc(N3CCOCC3)cc2n1Cc1ccccc1Cl

Procedure:
The titled compound was prepared from 4-(4-bromo-1-(2-chlorobenzyl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.2 g, 0.475 mmol) using Method A with trimethylborate to give the product (0.272 g, 39%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.77 (s, 3H) 3.15-3.25 (m, 4H) 3.65-3.82 (m, 4H) 5.75 (s, 2H) 6.82-6.88 (m, 1H) 7.22-7.30 (m, 1H) 7.32-7.40 (m, 2H) 7.56 (dd, J=7.96, 1.14 Hz, 1H) 7.80 (d, J=1.95 Hz, 1H); MS (ES+) 386.0 m/z
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([S:31]([N:34]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[C:35]4[S:36][CH:37]=[CH:38][N:39]=4)(=[O:33])=[O:32])=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)=[C:17]([OH:49])[CH:16]=1>CN(C=O)C.CCOC(C)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([S:31](=[O:32])(=[O:33])[N:34]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[C:35]4[S:36][CH:37]=[CH:38][N:39]=4)=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)=[C:17]([CH:16]=1)[O:49][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4O)nccc3c2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(F)ccc1-c1nccc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of Cs2CO3 (0.281 g, 0.863 mmol), ethyl bromoacetate (0.048 ml, 0.431 mmol) and 1-(4-fluoro-2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (From Step 1 in Example 189; 0.15 g, 0.288 mmol) in DMF (2.88 ml) was stirred at 60° C. for 16 h. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (2×50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography (25 g column), eluting with EtOAc:Hex: 0-50% to obtain ethyl 2-(5-fluoro-2-(6-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)phenoxy)acetate as light yellow solid. m/z (ESI) 608.3 (M+H)+.
Reaction SMILES: [C:1](=[O:28])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[CH:11][N:10]=2)[CH2:5][CH2:4]1.[CH:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>N1C=CC=CC=1>[CH:29]([N:32]1[CH2:37][CH2:36][N:35]([C:1]([O:2][CH:3]2[CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[CH:11][N:10]=3)[CH2:7][CH2:8]2)=[O:28])[CH2:34][CH2:33]1)([CH3:31])[CH3:30]
Reactant: NC(=O)c1ccc(N2CCC(OC(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)nc1
Reactant: CC(C)N1CCNCC1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)OC2CCN(c3ccc(C(N)=O)cn3)CC2)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To the solution of 1-(5-carbamoylpyridin-2-yl)-piperidin-4-yl 4-nitrophenyl carbonate (3.0 g, 7.77 mmol) in pyridine (50 ml) was added 1-isopropylpiperazine (1.05 g, 8.16 mmol) and DIPEA (2.01 g, 15.5 mmol). The resulting mixture was stirred at 30° C. for 2 h before it was concentrated to dryness. The residue was further purified by silica gel chromatography (DCM: MeOH=50:1 to 5:1) to afford the title compound as a white solid (1.46 g, 50%). MP: 200.1-203.6° C. [1H NMR (DMSO, 500 MHz): δ 8.61 (d, J=2 Hz, 1H), 7.95 (dd, J=2.5 Hz, 9 Hz, 1H), 7.53 (s, 1H), 7.12 (s, 1H), 6.87 (d, J=9.5 Hz, 1H), 4.83 (m, 1H), 3.90-3.85 (m, 2H), 3.54-3.49 (m, 2H), 3.34 (s, 4H), 2.67-2.64 (m, 1H), 2.38 (m, 4H), 1.89-1.85 (m, 2H), 1.58-1.54 (m, 2H), 0.95 (d, J=6.5 Hz, 6H); LCMS RtA=1.61 min, [M+H]+=376.3].
Reaction SMILES: [CH3:1][C:2]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15](C3C=CN=C(C(OC)=O)C=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].BrC1C=CN=C(C(OC)=O)C=1.C([O:49][CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][N:60]2[CH:64]=[C:63](Br)[CH:62]=[N:61]2)[CH:54]=1)(=O)C>>[CH3:1][C:2]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:63]3[CH:62]=[N:61][N:60]([CH2:59][C:55]4[CH:56]=[CH:57][CH:58]=[C:53]([O:52][CH2:51][CH2:50][OH:49])[CH:54]=4)[CH:64]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: COC(=O)c1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cccc(C)c2C)ccn1
Reactant: CC(=O)OCCOc1cccc(Cn2cc(Br)cn2)c1
Agent: COC(=O)c1cc(Br)ccn1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCO)c5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to methyl 4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)picolinate except that methyl 4-bromopicolinate was replaced with 2-(3-((4-bromo-1H-pyrazol-1-yl)methyl)phenoxy)ethyl acetate. LCMS, [M+H]+=540.4.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].O.[OH-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:7][NH:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:16]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)NNC(=O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a suspension of t-butyl hydrazine hydrochloride (6.2 g, 0.05 mole), water (30 mL) and toluene (60 mL) at 0° C. to 5° C. was added 50% sodium hydroxide (4.0 g,0.05 mol). To the above reaction mixture was then added, separately and simultaneously, 50% sodium hydroxide (4.0 g,0.05 mol) and 3-chlorobenzoyl chloride (8.8 g, 0.05 mol) from two dropping funnels. After addition was completed, the reaction mixture was stirred at 0° C. for 30 minutes and room temperature for 30 minutes. The resultant precipitate was collected by suction-filtration and washed with water (100 mL) and dried in air to give 9.0 g (79% yield) of 1-(3-chlorobenzoyl)-2-t-butyl hydrazine as a white solid. mp 116°-118° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:26])=[C:12]([NH:14][C:15]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]4=[N:19][CH:18]=3)=[O:16])[CH:13]=2)[N:4]=1.CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:36][S:37]([O:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:26])=[C:12]([NH:14][C:15]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]4=[N:19][CH:18]=3)=[O:16])[CH:13]=2)[N:4]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(-c2noc(CO)n2)cc1NC(=O)c1cnc2ccccn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2noc(COS(C)(=O)=O)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
To a solution of N-(5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (43) (210 mg, 0.6 mmol) and DIEA (0.32 mL, 1.8 mmol) in DCM (5 mL) was added MsCl (138 mg, 1.2 mmol). The mixture was stirred at room temperature for 10 minutes then subjected to standard aqueous work up. The crude product was purified by silica chromatography to yield (3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methyl methanesulfonate (44) (180 mg, 70% yield). MS m/z 428.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7](=S)/[N:8]=[C:9]1\[S:10][C:11]2[C:21]([CH3:23])([CH3:22])[O:20][CH2:19][CH2:18][C:12]=2[N:13]\1[CH2:14][CH:15]([CH3:17])[CH3:16].C(N(CC)CC)C.[N:35]#[C:36][NH2:37]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C:7](=[N:37][C:36]#[N:35])/[N:8]=[C:9]2\[S:10][C:11]3[C:21]([CH3:23])([CH3:22])[O:20][CH2:19][CH2:18][C:12]=3[N:13]\2[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:25]=1
Reactant: N#CN
Reactant: COc1ccc(Cl)cc1C(=S)/N=c1\sc2c(n1CC(C)C)CCOC2(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(Cl)cc1C(=NC#N)/N=c1\sc2c(n1CC(C)C)CCOC2(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a solution of Example 89H (0.18 g, 0.42 mmol) in acetonitrile (10 mL) were added mercuric acetate (0.18 g, 0.55 mmol, Aldrich), triethylamine (0.18 mL, 1.27 mmol) and cyanamide (0.04 g, 0.85 mmol, Aldrich). After stirring at 80° C. for 16 hr, the reaction mixture was cooled and quenched with saturated NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined the organic extracts were washed with water (1×25 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-50% ethyl acetate in hexanes) and followed by crystallization from ethyl acetate/hexanes to afford 0.04 g (21%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86 (d, J=6.8 Hz, 6H), 1.51 (s, 6H), 2.06-2.35 (m, 1H), 2.66-2.87 (m, 2H), 3.81 (s, 3H), 3.94-4.14 (m, 4H), 7.21 (d, J=9.2 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.52 (dd, J=9.2, 2.7 Hz, 1H); MS (ESI+) m/z 433 (M+H)+; Anal. Calculated C21H25ClN4O2S: C, 58.25; H, 5.82; N, 12.94. Found: C, 58.30; H, 5.79; N, 12.64.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:39])[F:38])[CH:31]=1)[NH2:25]>C(O)(C)C.C(OCC)(=O)C>[CH3:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:38])([F:39])[F:40])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Cl)c21
Reactant: Cc1cc(N)ccc1Oc1cccc(OC(F)(F)F)c1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2ncnc3ccn(CCNC(=O)OC(C)(C)C)c23)ccc1Oc1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 103.5 %

Procedure:
tert-Butyl [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (297 mg) and 3-methyl-4-[3-(trifluoromethoxy)phenoxy]aniline (425 mg) were dissolved in isopropyl alcohol (2.97 mL), and the mixture was stirred at 80° C. for 16 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate (60 mL), and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) to give the title compound (563 mg) as a white powder.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH2:30][CH2:29][C:27](=[O:28])[NH:26][C:24]=4[CH:25]=3)[CH2:11][CH2:10]2)[C:4]([Cl:8])=[C:5]([Cl:7])[CH:6]=1.[H-].[Na+].Cl[C:34]([O:36][CH2:37][Cl:38])=[O:35]>CC1CCCO1.C(OCC)(=O)C>[Cl:8][C:4]1[C:5]([Cl:7])=[CH:6][CH:1]=[CH:2][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[C:24]3[C:23]([CH2:30][CH2:29][C:27](=[O:28])[N:26]3[C:34]([O:36][CH2:37][Cl:38])=[O:35])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: O=C(Cl)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)OCCl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of aripiprazole (2 g, 4.46 mmol) in 2-methyltetrahydrofuran (40 mL) was added NaH (357 mg, 8.92 mmol). After 20 minutes, further 2-methyltetrahydrofuran (20 mL) was added to aid stirring. Chloromethyl chloroformate (1.19 mL, 13.38 mmol) was then added and the reaction stirred for 2 days. The reactions were combined for work up. The reaction was cooled to 0° C., diluted with ethyl acetate (50 mL) and quenched with aqueous saturated NaHCO3 solution (50 mL). The reaction was extracted with ethyl acetate (3×50 mL) and the combined organics washed with brine (100 mL), then dried (MgSO4) and concentrated to give chloromethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (crude yield 2.59 g) as 3:2 mixture of product/aripiprazole. The product was not purified due to instability during silica chromatography and so taken onto the next step crude.
Reaction SMILES: FC1C=C(CN)C=NC=1.[CH3:10][C:11]1[N:16]=[C:15]([CH2:17][NH2:18])[CH:14]=[N:13][CH:12]=1.[CH2:19]([N:23]1[CH2:27][CH2:26][N:25]([C:28]2[S:29][C:30]([C:34](O)=[O:35])=[C:31]([CH3:33])[N:32]=2)[C:24]1=[O:37])[CH:20]([CH3:22])[CH3:21]>>[CH2:19]([N:23]1[CH2:27][CH2:26][N:25]([C:28]2[S:29][C:30]([C:34]([NH:18][CH2:17][C:15]3[CH:14]=[N:13][CH:12]=[C:11]([CH3:10])[N:16]=3)=[O:35])=[C:31]([CH3:33])[N:32]=2)[C:24]1=[O:37])[CH:20]([CH3:22])[CH3:21]
Reactant: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)O
Reactant: Cc1cncc(CN)n1
Agent: NCc1cncc(F)c1
Product: Cc1cncc(CNC(=O)c2sc(N3CCN(CC(C)C)C3=O)nc2C)n1
Yield: 46 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with (6-methylpyrazin-2-yl)methanamine to react with 2-(3-isobutyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 46% yield: mp 139-142° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.50 (s, 1H), 8.38 (s, 1H), 6.75-6.72 (m, 1H), 4.69 (d, J=5.0 Hz, 2H), 4.14-4.08 (m, 2H), 3.62-3.56 (m, 2H), 3.13 (d, J=7.4 Hz, 2H), 2.62 (s, 3H), 2.56 (s, 3H), 1.98-1.88 (m, 1H), 0.94 (d, J=6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 162.6, 157.7, 155.7, 153.1, 152.5, 148.7, 143.4, 142.7, 117.1, 51.5, 42.9, 42.3, 42.0, 26.8, 21.2, 19.9, 17.2; MS (ES+) m/z 388.8 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O-:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][CH2:43][C:44]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:45]=1[CH:46]=[N:47][N:48]2[CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][O:54]1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:42][CH2:43][C:44]2[CH:52]=[CH:51][CH:50]=[C:49]3[C:45]=2[CH:46]=[N:47][N:48]3[CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][O:54]2)=[O:10])[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1Cl
Reactant: NCc1cccc2c1cnn2C1CCCCO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(=O)NCc2cccc3c2cnn3C2CCCCO2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
2-Chloro-1,4-benzenedicarboxylic acid, 1-methyl ester (Example 1; 84.3 mg, 0.393 mmol) was suspended in dichloromethane (1.5 mL) and the mixture was cooled to 0° C. BOP reagent (191 mg, 0.432 mmol) was added in one portion, followed by 4-aminomethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Example 12; 91 mg, 0.393 mmol) with a 2×0.25 mL wash of dichloromethane. Diisopropylethylamine (0.21 g, 1.62 mmol) was added over 1 min at ˜0° C. The mixture was stirred at ˜0° C. for 30 min and then at room temperature for 3.5 h. The mixture was concentrated to remove dichloromethane, and ethyl acetate (60 mL) was added. The solution was washed with 1 M HCl, sodium hydrogen carbonate solution, and brine (10 mL each), then dried (MgSO4), filtered, and concentrated. Ethyl acetate/petroleum ether was added and the insoluble material was filtered off to give 2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoic acid, methyl ester (93 mg, 55%) as a white solid.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.CCCCCC.[CH3:35][O:36][N:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1>C1COCC1>[CH3:35][O:36][N:37]1[CH2:42][CH2:41][C:40](=[CH:2][O:3][CH3:4])[CH2:39][CH2:38]1
Reactant: CON1CCC(=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC=C1CCN(OC)CC1
Temperature: -60 °C
Reaction time: 0.33 h

Procedure:
A mixture of (methoxymethyl)triphenylphosphonium chloride (35.8 g, 104 mmol) in THF (160 mL) was cooled to −60° C. and treated with a 2.5M solution of n-BuLi in hexane (42 mL, 105 mmol). After 20 min, a solution of 1-methoxy-piperidin-4-one [prepared according to Journal of Organic Chemistry (1961), 26, 1867-74] (9 g, 70 mmol) in THF (80 mL) was added, and the reaction mixture was allowed to warm to 10° C. over 2 h. The reaction was quenched with saturated ammonium chloride, and the solvent was removed under reduced pressure. The residue was partitioned between water and chloroform and the organic layer dried with sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel. Yield: 9.2 g of 1-methoxy-4-methoxymethylene-piperidine as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[O:7].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOCC>[CH3:9][O:8][C:6](=[O:7])/[CH:5]=[CH:4]/[C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=1[O:1][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][Br:14]
Reactant: COC(=O)C=Cc1ccccc1O
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)/C=C/c1ccccc1OCCCCCBr

Procedure:
A mixture of 0.64 g (3.59 mmol) of methyl 2-hydroxycinnamate, 6.6. g (28.7 mmol) of 1,5-dibromopentane, 2 g (14.5 mmol) of anhydrous, granular potassium carbonate, and 25 mL of acetonitrile was stirred and refluxed for 24 hr. The resulting slurry was cooled, diluted with ether, and filtered with suction. The solids were washed well with ether. The filtrate and washes were combined and concentrated under reduced pressure. The oily residue was flash chromatographed on silica gel, eluting with 5:1 hexane-ether giving 1 g (85%) of (E)-3-[2-[(5-bromopentyl)oxy]phenyl]-2-propenoic acid methyl ester as a solid.
Reaction SMILES: N1CCOCC1.[C:7]([OH:11])(=[O:10])[CH:8]=O.[CH3:12][CH2:13][CH2:14][CH2:15][CH:16]=[O:17].Cl>CCCCCCC>[OH:17][CH:16]1[O:11][C:7](=[O:10])[CH:8]=[C:15]1[CH2:14][CH2:13][CH3:12]
Reactant: O=CC(=O)O
Reactant: CCCCC=O
Agent: Cl
Solvent: C1COCCN1
Solvent: CCCCCCC
Product: CCCC1=CC(=O)OC1O
Temperature: 0 °C

Procedure:
Heptane (394 mL) and morpholine (127.5 mL) are introduced in a reactor while stirring. The mixture is cooled to 0° C. and glyoxylic acid (195 g, 150 mL, 50 wt % in water) is added. The mixture is heated to 20° C. during 1 hour and then n-valeraldehyde (148.8 mL) is added. The reaction mixture is heated at 45° C. during 20 hours. After cooling down to 20° C., a 37% aqueous solution of hydrochloric acid (196.9 mL) is slowly added to the mixture, which is then stirred during 2 hours.