Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=3)[NH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CO.[H][H]>[N:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH2:16])[CH:14]=3)[NH:9][N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2[nH]nc(N3CCOCC3)c2c1
Solvent: CO
Product: Nc1ccc2[nH]nc(N3CCOCC3)c2c1
Reaction time: 24 h

Procedure:
3-Morpholin-4-yl-5-nitro-1H-indazole (210 mg) was dissolved in 10 ml of methanol and the mixture hydrogenated at 1 atm of hydrogen using 10% Pd/C (50 mg) as catalyst. After 24 hrs, the mixture was filtered and evaporated for use in the next step.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[F:29])[C:23](Cl)=[O:24]>C(Cl)Cl>[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[F:29])[C:23]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:24]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccccc1)c1ccc(F)c(F)c1
Reaction time: 1 h

Procedure:
To a stirred solution of phenethylamine (1.01 mL, 7.95 mmol) and DIEA (1.38 mL, 7.95 mmol) in 20 mL of DCM, 3,4-difluorobenzoyl chloride (1.00 mL, 7.95 mmol) was added dropwise. The clear solution was stirred for 1 h. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.57 (ddd, J=10.63, 7.56, 2.12 Hz, 1H) 7.31-7.44 (m, 3H) 7.15-7.31 (m, 4H) 6.02 (br. s., 1H) 3.67-3.78 (m, 2H) 2.94 (t, J=6.87 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]([S:36](Cl)(=[O:38])=[O:37])[CH:32]=[C:33]([F:35])[CH:34]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[S:36]([C:31]2[CH:30]=[C:29]([F:28])[CH:34]=[C:33]([F:35])[CH:32]=2)(=[O:38])=[O:37])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(S(=O)(=O)c4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VII as described above, the sulphonylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) with commercially available 3,5-difluorobenzenesulfonyl chloride gave the title compound.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:35])[C:6]1[C:7](=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24](=[O:34])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)=[CH:14][CH:15]=1)[C:8]([O:10]C)=[O:9].Cl>O1CCOCC1>[N+:31]([C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][C:13]1[CH:12]=[C:7]([C:8]([OH:10])=[O:9])[C:6](=[CH:15][CH:14]=1)[C:5]([OH:35])=[O:4])=[O:34])([O-:33])=[O:32]
Reactant: COC(=O)c1ccc(Oc2ccccc2NC(=O)c2cccc([N+](=O)[O-])c2)cc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1Oc1ccc(C(=O)O)c(C(=O)O)c1)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 68.6 %

Procedure:
2N sodium hydroxide (12 ml) was added to a solution of 4-(2-(3-nitrobenzoylamino)-phenoxy)phthalic acid dimethylester (1.15 g, 2.83 mmol) in 1,4-dioxan (12 ml) at room temperature. The mixture was stirred for 2 hours, cooled to <10° C. and pH adjusted to 2-3 with 1N hydrochloric acid (approx. 24 ml). The resulting crystals were filtered off and washed with water. The crystals were dried to give beige crystals of 4-[2-(3-nitrobenzoylamino)-phenoxyl]phthalic acid (yield: 0.82 g. (76%)). 1H—NMR (CDCl3) in ppm: δ 10.3 (s, 1H), 8.38 (m, 1H), 8.18 (d, 1H), 7.6-7.8 (m, 3H), 7.3-7.4 (m, 2H), 7.18 (d.d., 1H), 7.1 (m, 1H), 7.07 (d.d., 1H). Mp: 199.7-201.0° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:26]#[N:27])=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[CH2:8]1.O=[C:29]([CH3:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:34]([O:33][C:31]([C:30]1[C:29]([CH3:36])=[N:1][C:2]2[C:3]([C:26]=1[NH2:27])=[C:4]([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)[CH:23]=[CH:24][CH:25]=2)=[O:32])[CH3:35]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OCC1CCCN(C(=O)OCc2ccccc2)C1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCNC3)c2c1N

Procedure:
Prepared as in Example 2a from benzyl 3-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example 110c) and ethyl 3-oxobutanoate as a yellow oil (21%). MS 344 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[O:14])([O-:3])=[O:2].[CH2:15](O)[CH2:16][CH2:17][OH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]12[O:18][CH2:17][CH2:16][CH2:15][O:14]1)([O-:3])=[O:2]
Reactant: OCCCO
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C12OCCCO2

Procedure:
A mixture of 5-nitroisatin (5.00 g, 26.0 mmol), 1,3 propandiol (4.76 mL , 65 mmol, 2.5 eq) and p-toluenesulfonic acid mono-hydrate (0.989 g, 5.2 mmol, 0.2 mol %)) in benzene (500 mL) was refluxed with a Dean Stark Trap for 23 hr. The benzene was decanted off and concentrated. The crude product was purified on Biotage KP silica gel eluting with 50/50 petroleum ether/EtOAc to give the title compound as an off white solid (1.78 g, 27% yield). NMR (300 Mz, DMSO-d6): consistent.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1.[CH2:18]([NH:22][CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH2:37][CH3:38])[CH:25]=1)[CH2:19][CH2:20][CH3:21].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:18]([N:22]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH2:37][CH3:38])[CH:25]=1)[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1)[CH2:19][CH2:20][CH3:21]
Reactant: FC(F)(F)c1ccc(-c2cncc(Cl)n2)cc1
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(CC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(CC)c1)c1cncc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C
Yield: 17.3 %

Procedure:
A mixture of 2-chloro-6-[4-(trifluoromethyl)phenyl]pyrazine (0.172 g, 0.56 mmol), ethyl {4-[(butylamino)methyl]-2-ethylphenoxy}acetate (0.25 g, 0.85 mmol) and N,N-diisopropylethylamine (0.099 mL, 0.56 mmol) were heated together in a reactivial at 100° C. for 18 h. The vial was then allowed to cool to room temperature and the residue dissolved in CH2Cl2 (50 mL) and the organic solution washed with water (15 mL) and brine (10 mL). The solution was then passed through a hydrophobic frit and evaporated. Purification by Biotage™ chromatography (Silica, 40 g) eluting 9:1cyclohexane:EtOAc, afforded the title compound as a pale yellow oil (50 mg).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7].C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:16][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7]
Reactant: N#Cc1cc(CO)cc(C(F)(F)F)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1cc(CBr)cc(C(F)(F)F)c1
Yield: 84.6 %

Procedure:
To a solution (10 ml) of 3-hydroxymethyl-5-trifluoromethylbenzonitrile (1.00 g) and carbon tetrabromide (1.81 g) in dichloromethane was added triphenylphosphine (1.37 g) with stirring under ice-cooling, and the mixture was continuously stirred for 30 min. The reaction solution was concentrated and the obtained residue was purified by column chromatography (n-hexane:ethyl acetate=9:1) to give the title compound (1.11 g, 84%).
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](F)=[CH:13][CH:12]=1)#[N:10].C1CCN2C(=NCCC2)CC1>[OH-].[Na+]>[F:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: FC1CCCNC1
Reactant: N#Cc1ccc(F)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1ccc(N2CCCC(F)C2)c2ccccc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 18.3 %

Procedure:
3-Fluoropiperidine hydrochloride (106 mg, 0.76 mol) was dissolved in sodium hydroxide (1 M, 10 mL) and extracted with dichloromethane (4×10 mL), the combined extracts were dried over sodium sulfate, filtered and evaporated. Pyridine (2 mL) was added, followed by 1-cyano-4-fluoronaphthalene (108 mg, 0.63 mmol) and the vial was shaken at 110° C. overnight. GC-MS and TLC showed only very little conversion. DBU (10 μL) was added and the shaking was continued for 2 weeks at 110° C., after which GC-MS showed ˜50% conversion. The reaction was worked up in the same way as 165RL60 and purified by silica gel column chromatography eluted with a stepwise gradient of 0-60% ethyl acetate in n-heptane to give the title compound (29.3 mg, 12%) as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=O)[CH:8]=[CH:9][CH:10]=1.[Cl-].[CH2:16]([O:23][C:24]1[CH:49]=[CH:48][CH:47]=[CH:46][C:25]=1[CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:16]([O:23][C:24]1[CH:49]=[CH:48][CH:47]=[CH:46][C:25]=1[CH:26]=[CH:13][CH:12]=[CH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:6]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COCOc1cccc(C=CC=O)c1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COCOc1cccc(C=CC=Cc2ccccc2OCc2ccccc2)c1
Yield: 88.6 %

Procedure:
Following a procedure similar to that described in the first part of Preparation 3, 7.00 g of 3-(3-methoxymethoxyphenyl)-2-propenal and 18 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) were dissolved in 200 ml of acetonitrile, with heating, and 5.54 g of 1,8-diazabicyclo[5,4,0]undec-7-ene were added to the mixture and reacted. The crude product, extracted as described in Preparation 3, was purified as described in Preparation 3, to give 12.0 g of 1-(2-benzyloxyphenyl)-4-(3-methoxymethoxyphenyl)butadiene as a colorless oil.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:14])[O:13][CH2:12][CH2:11][CH2:10]1>>[OH:8][CH:1]([CH:10]1[CH2:11][CH2:12][O:13][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCO1
Product: O=C1OCCC1C(O)c1ccccc1

Procedure:
Benzaldehyde is reacted with γ-butyrolactone to produce 2-(1-hydroxy-1-phenylmethyl)-γ-butyrolactone.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:26][C:27]1[N:31]=[C:30]([C:32]2[C:33]([S:38][CH3:39])=[N:34][CH:35]=[CH:36][CH:37]=2)[O:29][N:28]=1>C(#N)C>[CH3:39][S:38][C:33]1[C:32]([C:30]2[O:29][N:28]=[C:27]([CH2:26][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])[N:31]=2)=[CH:37][CH:36]=[CH:35][N:34]=1
Reactant: CSc1ncccc1-c1nc(CCl)no1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccnc2SC)n1
Yield: 83.9 %

Procedure:
To a solution of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 153A) (0.100 g, 0.396 mmol) in anhydrous acetonitrile (20 mL) was added Cs2CO3 (1.30 g, 4.00 mmol) and 3-[3-(chloromethyl)-1,2,4-oxadiazol-5-yl]-2-(methylthio)pyridine (0.170 g, 0.594 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (0.152 g, 84% yield): MS (ES) m/z 458 (M+).
Reaction SMILES: Cl.[CH:2]1([C:5]2[CH:6]=[C:7]([CH3:17])[C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.[CH:18]([C@@H:21]1[CH2:25][O:24][C:23](=[O:26])[N:22]1[C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)([CH3:20])[CH3:19]>>[CH:2]1([C:5]2[CH:6]=[C:7]([CH3:17])[C:8]([N:11]3[CH2:12][CH2:13][N:14]([C:31]([C:30]4[CH:29]=[CH:28][C:27]([N:22]5[C@H:21]([CH:18]([CH3:19])[CH3:20])[CH2:25][O:24][C:23]5=[O:26])=[CH:35][CH:34]=4)=[O:32])[CH2:15][CH2:16]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: CC(C)[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C(C)C)cc2)CC1
Yield: 42.5 %

Procedure:
By reaction and treatment in the same manner as in Example 29 and using 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (381 mg) described in Preparation Example 49 and (R)-4-(4-isopropyl-2-oxooxazolidin-3-yl)benzoic acid (374 mg) described in Preparation Example 18, the title compound (286 mg) was obtained.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33](O)=[O:34])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][C:33]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=[CH:10]3)=[O:34])=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)CCc1ccc(Oc2ccccc2)cc1
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Product: O=C(CCc1ccc(Oc2ccccc2)cc1)Nc1ccc2c(cnn2CCN2CCCC2)c1

Procedure:
1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine and 3-(4-phenoxy-phenyl)-propionic acid were processed as described in Example 17 to provide the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 1.83 (m, 2 H), 1.99 (m, 2 H), 2.60 (t, J=7.64 Hz, 2 H), 2.87 (t, J=7.49 Hz, 2 H), 3.04 (m, 2 H), 3.52 (m, 2 H), 3.70 (m, 2 H), 4.73 (t, J=6.08 Hz, 2 H), 5.06 (s, 2 H), 6.92 (m, 2 H), 7.17 (m, 2 H), 7.32 (m, 1 H), 7.40 (m, 4 H), 7.49 (m, 1 H), 7.66 (m, 1 H), 8.13 (m, 2 H), 9.93 (s, 1 H); MS (DCI/NH3) m/z 469 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1O[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]=1)[CH3:2].[CH2:14]([CH2:16][NH2:17])[OH:15]>>[CH2:1]([C:3]1[N:17]([CH2:16][CH2:14][OH:15])[C:7](=[O:9])[C:6]2[C:5](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1)[CH3:2]
Reactant: NCCO
Reactant: CCc1nc2ccccc2c(=O)o1
Product: CCc1nc2ccccc2c(=O)n1CCO
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1 g of 2-ethyl-4H-3,1-benzoxazin-4-one was added to 10 mL of monoethanolamine and the mixture was heated to 100° C. for 40 minutes. The heating element was then removed and the reaction medium was kept under agitation for about eight hours (end of the reaction). 100 mL were added to the reaction medium and the mixture was extracted with three portions of 25 mL of ethyl acetate. The organic phase was separated, and dried with magnesium sulfate and spin dried, yielding the 2-ethyl-3-(2-hydroxyethyl)quinazoline-4 (3H)-one compound as a yellowish oil, which solidified when left to rest at room temperature, which was used in the next stage, with no purification.
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.C(N(CC)CC)C.[CH2:38]([N:45]=[C:46]=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[CH2:38]([NH:45][C:46]([N:26]1[C:24]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:2]=[CH:1][CH:6]=[C:5]([Cl:7])[C:4]=4[Cl:8])[CH2:10][CH2:11]3)[CH:25]=2)[CH2:30][CH2:29][C:27]1=[O:28])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of aripiprazole (1.5 g, 3.35 mmol) in dichloromethane (33 mL) was added triethylamine (0.56 mL, 4.01 mmol) and benzyl isocyanate (0.82 mL, 6.69 mmol). The reaction was stirred at room temperature for 48 hours. The reaction was quenched with water and extracted with dichloromethane (3×20 mL). The organics were combined, washed with brine (20 mL), dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica eluting with 0-10% tetrahydrofuran in ethyl acetate. The product was triturated in heptane to remove aliphatic impurities and then filtered and dried to afford Compound-79 (0.575 g) as a colorless solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH3:23])[CH:15]=1.[C:24](=O)([O:27]C)[O:25]C>C1COCC1>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH2:23][C:24]([OH:27])=[O:25])[CH:15]=1
Reactant: COC(=O)OC
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)Cc1cc(Br)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.8 %

Procedure:
To a solution of diisopropylamine (13.26 mL, 93 mmol, 4.0 equiv.) in THF (50 mL) was slowly added n-BuLi (37.2 mL, 93 mmol, 4.0 equiv.) at −78° C. The mixture was allowed to warm to 0° C. and stirred at that temperature for 5 min. The reaction was cooled back to −78° C. and to this mixture was slowly added 4-bromo-2-methylbenzoic acid (5.0 g, 23.25 mmol) and dimethyl carbonate (3.91 mL, 46.5 mmol, 2.0 equiv.) in THF (50 mL) and the mixture was stirred at −78° C. for 5 min. The dry ice bath was removed and the reaction was allowed to stir at room temperature for 4 h. Upon completion of the reaction, the mixture was quenched by the addition of 75 mL water and allowed to stir overnight. The aqueous layer was separated from the organic layer. The aqueous layer was acidified with conc. HCl until pH 2, extracted with EtOAc (2×50 mL), dried over Na2SO4, filtered and evaporated to dryness to yield a white solid. The solid was recrystallized from hot EtOAc/hexanes to yield 5.65 g of 4-bromo-2-(carboxymethyl)benzoic acid as a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH3:13][C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([NH:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]3[CH:30]=[C:31]([C:33](O)=[O:34])[S:32][C:25]=13)=[CH:18][CH:17]=2>>[CH3:13][C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([NH:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]3[CH:30]=[C:31]([C:33]([N:1]4[CH2:5][CH2:4][CH2:3][C@H:2]4[CH2:6][N:7]4[CH2:8][CH2:9][O:10][CH2:11][CH2:12]4)=[O:34])[S:32][C:25]=13)=[CH:18][CH:17]=2
Reactant: C1CN[C@H](CN2CCOCC2)C1
Reactant: Cc1cc2cc(Nc3ccnc4cc(C(=O)O)sc34)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC[C@H]5CN5CCOCC5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (S)-4-pyrrolidin-2-ylmethyl-morpholine and 7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridine-2-carboxylic acid by a procedure analogous to Example 21B. MS: 476.3 (MH+); HPLC Rf: 5.378 min.; HPLC purity: 92%.
Reaction SMILES: N=[S:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[C:13]([C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[O:19][C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1)([CH3:16])([CH3:15])[CH3:14]>CO>[C:13]([C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[O:19][C:20]1[C:25]([NH:26][C:3]2[S:2][C:6]3[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=3[N:4]=2)=[CH:24][CH:23]=[CH:22][N:21]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc2c(c1)S(=N)C=N2
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N
Solvent: CO
Product: COc1ccc2nc(Nc3cccnc3Oc3ccccc3C(C)(C)C)sc2c1
Temperature: 25 °C

Procedure:
100 mg (0.38 mmol) of 1-imino-6-methoxybenzothiazole and 1b were heated under N2 atmosphere at 220° C. for 30 min, in a similar manner to 234a. After cooling to rt, the reaction mixture was suspended in MeOH and the side product bis(6-methoxybenzo[d]thiazol-2-yl)amine (46.3 mg) was eliminated by filtration. The mother liquors were purified by preparative HPLC to yield Example 233. tR=7.861 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna 4.6×50 mm; flow rate 2.5 mL/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4 & B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C23H24N3O2S [M+H]+406.1589, found 406.1576.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])[CH2:22][CH2:21]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)c4ccccc4)CC3)n[nH]c12
Yield: 8.9 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (0.057 g, 0.17 mmol) was reacted with phenylsulfonyl chloride (0.022 mL, 0.17 mmol) in the presence of triethylamine (0.1 mL, 0.71 mmol) and DMAP (0.0021 g, 0.017 mmol) in DMF (3 mL) to give 0.007 g of pale yellow solid.