Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[OH:41])([CH3:4])([CH3:3])[CH3:2].[C:43](O)(=[O:50])[C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>>[C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[O:41][C:43]([C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1)=[O:50])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccncc1
Reactant: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Product: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(OC(=O)c2ccncc2)c1
Yield: 86.3 %

Procedure:
The title compound was prepared according to the procedure in Example 25, step 1, using 4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2, 6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.500 g, 0.691 mmol), isonicotinic acid (0.0851 g, 0.691 mmol), 2-chloro-1-methylpyridinium iodide (0.212g, 0.829 mmol) and triethylamine (0.327 mL, 2.35 mmol). Purification on Biotage KP-Sil eluting with 25% EtOAc/hexane gave 0.461 g (86%) of the title compound. 1H NMR (DMSO-d6) δ 1.35 (s, 9 H), 1.54 (s, 3 H), 2.17 (s, 6 H), 2.36 (s, 3 H), 7.19 (s, 2 H0, 7.45-7.47 (m, 2 H), 7.61-7.66 (m, 1 H), 8.04 (dd, 2 H), 8.13-8.25 (m, 4 H), 8.92 (dd, 2 H). mass spectrum (+ESI) m/z 772/774 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:8][C:6]1[CH:5]=[C:4]([O:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Brc1ccccc1
Reactant: Cc1cc(C)cc(O)c1
Product: Cc1cc(C)cc(Oc2ccccc2)c1
Yield: 98 %

Procedure:
Following General Procedure A (90° C., 30 hours), 3,5-dimethyl phenol (183 mg, 1.5 mmol) is coupled with bromo-benzene (106 μL, 1.0 mmol) to give 98% 1,3-dimethyl-5-phenoxybenzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].CI.[C:13]([O-])([O-])=O.[K+].[K+]>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:13])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(Br)ccc1O
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc(Br)cc1C#N

Procedure:
A mixture of 5-bromo-2-hydroxybenzonitrile (1 g, 5 mmol), MeI (0.85 g, 6 mmol) and K2CO3 (2 g, 15 mmol) in 25 mL of dry CH3CN were heated to refluxed over night. The solvent was evaporated off and the residue was added water. Extracted the mixture with DCM and the organic layer was washed with saturated chloride, dried over Na2SO4. The residue was purified with fast column chromatograph to afford compound 5-bromo-2-methoxybenzonitrile.
Reaction SMILES: [H-].[Na+].[CH:3]([NH:7][C:8]([CH:10]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=1)[C:11]([CH3:19])([CH3:18])[CH2:12]OS(C)(=O)=O)=[O:9])([CH2:5][CH3:6])[CH3:4]>C1COCC1.CO>[C@@H:3]([N:7]1[CH2:19][C:11]([CH3:18])([CH3:12])[C@@H:10]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([C:29]([F:31])([F:32])[F:30])[CH:22]=2)[C:8]1=[O:9])([CH2:5][CH3:6])[CH3:4]
Reactant: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)COS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H](C)N1CC(C)(C)[C@@H](Oc2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 22.5 °C
Reaction time: 90 h

Procedure:
Solid NaH (60 wt % dispersion in mineral oil, 16.6 g, 416 mmol) was added portion wise over 25 min to a cold (0-5° C.) sol'n of methanesulfonic acid 3-sec-butylcarbamoyl-3-(4-cyano-3-trifluoromethylphenoxy)-2,2-dimethylpropyl ester (104 g, 208 mmol) in 400 mL dry THF under an N2 atmosphere. The reaction mixture was allowed to warm to 20-25° C. and then stirred at this temp. for 90 h. The reaction mixture was quenched by adding it to 500 mL cold (5-10° C.) sat'd aq. NH4Cl. The phases were separated and the aqueous was extracted with ethyl acetate (“EtOAc”) (2×500 mL). The pale yellow organic was conc'd under vac (40-45° C.) to an orange-yellow oil/gum (83 g). The crude product was purified by extensive silica gel (230-400 mesh) column chromatography (EtOAc/Heptane) followed by crystallization (EtOAc/Heptane). The pure desired diastereomer was isolated as a white granular solid MS+: 355. m.p. 101-102° C. Optical rotation [α]58925=+180.10(in methanol) Elemental analysis results: Obsv'd (Theor.): C, 61.03 (61.01); H, 6.02 (5.97); N, 7.88 (7.91); F, 15.98 (16.08). HPLC analysis: Chiral purity: 100%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:4]=1/[CH:5]=[CH:6]/[C:7](Cl)=[O:8].[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:22]([O:24][CH3:25])=[O:23]>C(Cl)Cl.N1C=CC=CC=1>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:28]([CH3:29])=[C:19]([NH:18][C:7](=[O:8])[CH:6]=[CH:5][C:4]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([O:14][CH3:15])[C:3]=2[O:2][CH3:1])[CH:20]=1
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: COc1ccc(/C=C/C(=O)Cl)c(OC)c1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(NC(=O)C=Cc2ccc(OC)c(OC)c2OC)c1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve trans-2,3,4-Trimethoxycinnamic acid (50) (200 mg, 0.84 mmol) in anhydrous DCM (4.4 mL) at it and add anhydrous DMF (3 drops, cat. amount). Then add slowly oxalyl chloride (96 μL, 1.09 mmol) stir the turbid mixture for additional 2 h at rt. Remove solvent and dry the residue in oil pump vacuum to obtain trans-2,3,4-Trimethoxycinnamic acid chloride (51) (ca. 0.84 mmol) as an yellow solid. Dissolve acid chloride (51) (108 mg, 0.42 mmol) in anhydrous DCM (4.0 mL) and add it to an ice cooled solution of Methyl 3-amino-4-methylbenzoate (52) (69 mg, 0.42 mmol) in anhydrous DCM (2.0 mL) and anhydrous pyridine (1.2 mL). Stir the resulting reaction mixture at rt overnight. Pour the reaction mixture into ice cooled 1M aqu. HCl, extract with EtOAc (3×), wash the combined organic layer with brine and dry it with Na2SO4. Purify the crude product by filtration through a short pad of silica gel with EtOAc and remove solvent to obtain 4-Methyl-3-[3-(2,3,4-trimethoxy-phenyl)-acryloylamino]-benzoic acid methyl ester (53) (99 mg, 61%) as a light yellow solid. 1H NMR (400 MHz, CDCl3): 2.35 (s, 3H); 3.87 (s, 3H); 3.88 (s, 6H); 3.91 (br.s, 3H); 6.59 (d, 1H, J=15.6 Hz); 6.68 (d, 1H, J=8.6 Hz); 7.08 (br.s, 1H); 7.20-7.29 (m, 2H); 7.77 (br.d, 1H, J=8.6 Hz); 7.90 (d, 1H, J=15.6 Hz); 8.55 (br.s 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:29][C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:20][CH:19]4[N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:10]=2)=[N:6][CH:7]=1.[SH:37][CH2:38][C:39]([O:41][CH3:42])=[O:40]>>[CH3:42][O:41][C:39](=[O:40])[CH2:38][S:37][C:2]1[CH:3]=[C:4]([O:29][C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:20][CH:19]4[N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:10]=2)=[N:6][CH:7]=1
Reactant: COC(=O)CS
Reactant: Cc1ncccc1Oc1cc(Br)cnc1Nc1nc(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)ns1
Product: COC(=O)CSc1cnc(Nc2nc(C3CC4CCC(C3)N4C(=O)OC(C)(C)C)ns2)c(Oc2cccnc2C)c1
Yield: 84 %

Procedure:
Following the procedure in Example 52, tert-butyl 3-(5-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (526 mg, 0.917 mmol) and methyl 2-mercaptoacetate (92.3 μL, 1.01 mmol) afforded tert-butyl 3-(5-(5-(2-methoxy-2-oxoethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (461 mg, 0.770 mmol, 83.9% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]2[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:19][C:11]1=2)([O-])=O>[Pd].CCO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]2[C:17]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:19][C:11]1=2
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccccc2[N+](=O)[O-])c1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccccc2N)c1-c1ccccc1
Reaction time: 45 h
Yield: 60.9 %

Procedure:
A mixture of the compound of Example 120 (455 mg, 1.08 mmol) and palladium on charcoal (10% Pd wt/wt, 90 mg) in EtOH (20 mL) was stirred under an atmosphere of hydrogen (balloon) for 45 h. The catalyst was filtered off and the filtrate concentrated in vacuo. Purification by column chromatography on silica (3% to 5% THF in DCM) gave the title compound as a pale yellow solid (257 mg, 61%). δH (DMSO-d6) 7.59–7.52 (3H, m), 7.48–7.44 (3H, m), 7.33–7.28 (1H, m), 7.16 (1H, dd, J 1.5, 7.8 Hz), 6.98 (1H, dd, J 1.2, 8.2 Hz), 6.77–6.73 (1H, m), 6.59 (1H, d, J 9.6 Hz), 5.33 (2H, br s), 4.12 (2H, q, J 7.1 Hz), 1.12 (3H, t, J 7.1 Hz). ). LCMS (ES+) RT 3.581 minutes, 391.0 (M+H)+.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH:8]([N:10]2[C:23]3[CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:27]1([CH2:31][NH2:32])[CH2:30][CH2:29][CH2:28]1>ClCCl>[CH:27]1([CH2:31][NH:32][C:24]([C:21]2[CH:20]=[CH:19][C:18]3[S:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH:8]([CH2:7][N:2]4[CH2:3][CH2:4][CH2:5][CH2:6]4)[CH3:9])[C:23]=3[CH:22]=2)=[O:25])[CH2:30][CH2:29][CH2:28]1
Reactant: NCC1CCC1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)O)cc21
Agent: Cl
Solvent: ClCCl
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)NCC3CCC3)cc21
Yield: 46.4 %

Procedure:
Using a procedure similar to that described in Example 15, but starting with 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxylic acid hydrochloride (3.4 g) in dichloromethane (100 cc) and cyclobutylmethylamine (4.5 g), and after recrystallization in isopropyl ether, N-cyclobutylmethyl-10-[(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (1.7 g) is obtained in the form of white crystals, m.p. 133° C.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.[BH4-].[Na+]>C1COCC1.CO>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C@@H:12]([OH:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12

Procedure:
This synthesis is depicted in FIG. 1. Ketone 1 (500 mg, 1.84 mmol) was reduced with sodium borohydride (d, 75 mg, 2 mmol) in THF/MeOH 5:1 (18 ml) at RT. (2 h). The crude product was chromatographed on silica gel (60 g) using toluene/ethyl acetate 2:1. After traces of the axial alcohol 2 (9 mg, 2%), the pure equatorial alcohol 3 (388 mg, 77%) was eluted. An analytical sample was recrystallized from MeOH/water. M.p. 124°-125°, [a]D =+14.2° (c=1.12) ([2]: m.p, 125°-127°, [a]D17 =+11.2° (c=0.76)). - IR. (CDCl3): 3620m, 3430w, 1590w. - 1H-NMR. (360 Mhz): 0.77 (s, 3 H); 0.85 (s, 3 H); 3.60 t x t, J=11 and 5, 1 H); 5.70 (m, 1 H); 5.84 (m,1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:5]2[CH2:20][C:21]([OH:23])=O.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:5]2([CH:20]=[C:21]=[O:23])[N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]1
Reactant: Cc1cc2c(cc1C)C(CC(=O)O)N(c1cccc(F)c1)C2=O
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(cc1C)C(C=C=O)(N1CCN(C)CC1)N(c1cccc(F)c1)C2=O
Yield: 89 %

Procedure:
5,6-dimethyl-2-(3-fluorophenyl)-3-carboxymethyl-isoindolin-1-one [IUPAC name: 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]acetic acid] (0.50 g, 1.6 mmol), 1-methylpiperazine (0.16 g, 1.6 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.31 g, 1.6 mmol) and 1-hydroxybenzotriazole hydrate (0.25 g, 1.6 mmol) were stirred in tetrahydrofuran (40 ml) at 25° C. for 16 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give 0.56 g of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]2([C:14]#[N:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(c2ccc(Cl)cc2)CCNCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
To a chilled solution of 4-(4-chloro-phenyl)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (315 mg, 1 mmol) in 5 ml dichloromethane was added 1 ml trifluoroacetic acid. The reaction was stirred at 0° C. for 3 hours, then concentrated under vacuum. The resulting oil was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate. The aqueous washings were extracted three times with dichloromethane. The combined organic layers were dried with magnesium sulfate and concentrated under vacuum to yield the title compound (180 mg, 82%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[OH:22]
Reactant: Brc1cccc2c1OCC2
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1cccc2c1OCC2
Yield: 72.2 %

Procedure:
With 3.00 g of 7-bromo-2,3-dihydro-1-benzofuran and 1.10 g of 5-chloroisatin as starting material, 1.32 g of the title compound (white solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][C:10]=1Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Li].C([Li])(C)(C)C.CN(C)[CH:33]=[O:34]>O.CCOCC>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][C:10]=1[CH:33]=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OC(C)(C)C)c(Br)c1
Reactant: CN(C)C=O
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OC(C)(C)C)c(C=O)c1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3.3 g (0.01 mol) 2,5-bis-tert.-butyloxycarbonylaminobromobenzene from step A are dissolved in 100 ml of water-free tetrahydrofuran under argon. 17 ml of a 1.6 molar etheric methyl lithium solution (0.03 mol) are gradually added. The reaction mixture is cooled to −20° C., 7 ml of a 1.5 molar tert.-butyl lithium solution (0.01 mol) are gradually added. After the addition has ended the solution is stirred for 30 minutes at the given temperature. Subsequently 1.2 g of dimethyl formamide (0.02 mol) are added and the reaction mixture is stirred for one hour at −20° C. After slowly heating to room temperature the reaction mixture is hydrolyzed with water and then poured into ether, the aqueous phase is extracted with ether and then the organic phase is dried over magnesium sulfate. The solvent is distilled away in a rotary evaporator and the residue is purified on silica gel with a petroleum ether/ethyl acetate solvent (9/1).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:3]1.[ClH:24]>O1CCCC1.O1CCOCC1>[ClH:24].[O:1]=[C:2]1[CH2:6][NH:5][C@H:4]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C1CN[C@H](C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of (S)-2-benzyl 1-tert-butyl 4-oxopyrrolidine-1,2-dicarboxylate (2.82 g, 8.8 mmol) in anhydrous tetrahydrofuran (44 mL) was added 4N HCl in 1,4-dioxane (9.3 mL) at room temperature. The mixture was stirred for 18 hours at room temperature. The product was then three times with toluene on rotovap to dryness to remove all the excess acid and further dried on a high vacuum overnight and used as is in the next step. Quantitative yield.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: Cc1csc(Nc2cc(OC3CCCN(C(=O)OC(C)(C)C)C3)ccn2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1csc(Nc2cc(OC3CCCNC3)ccn2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)piperidine-1-carboxylate (1.65 g, 4.23 mmol) in dichloromethane (10 mL), and 2,2,2-trifluoroacetic acid (0.977 mL, 12.7 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. A saturated solution of NaHCO3 was added, and the solution was extracted with EtOAc and dichloromethane. The combined organic layers were filtered and concentrated to provide 4-methyl-N-(4-(piperidin-3-yloxy)pyridin-2-yl)thiazol-2-amine as a light yellow solid. (0.70 g, 53.6% yield). Mass spectrum (apci) m/z=291 (100) (+H).
Reaction SMILES: C(O[CH:4]=[CH:5][C:6](=O)[C:7]([F:10])([F:9])[F:8])C.[CH3:12][NH:13][NH2:14]>CO>[CH3:12][N:13]1[CH:4]=[CH:5][C:6]([C:7]([F:10])([F:9])[F:8])=[N:14]1
Reactant: CNN
Reactant: CCOC=CC(=O)C(F)(F)F
Solvent: CO
Product: Cn1ccc(C(F)(F)F)n1
Temperature: 25 °C

Procedure:
To a mixture of 18 g of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one and 50 ml of methanol was added 5.7 ml of methylhydrazine, and the mixture was heated to reflux for 4 hours. The reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure, and subjected to distillation under reduced pressure (60° C./15 mmHg) to obtain 8.71 g of 1-methyl-3-trifluoromethyl-1H-pyrazole of the formula:
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:12])=O>>[Br:1][C:2]1[C:3]([Cl:12])=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ncc(Br)c(Cl)n1
Temperature: 120 °C

Procedure:
5-Bromo-2-methylpyrimidin-4-ol (5 g, 2.6 mmol) was suspended in phosphorous oxychloride (100 mL). The reaction mixture was heated at 120° C. for 60 minutes. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and azeotroped twice with toluene. The crude residue was diluted with EtOAc (100 mL) and cooled to 0° C. Aqueous sodium bicarbonate (20 mL) was slowly added with stirring. The organic layer was washed once more with sodium bicarbonate (20 mL), dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a dark oil, which was sufficiently pure to use in the subsequent step without further purification (5.3 g, 98%): LC/MS m/z=207.0 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]2[NH:22][N:23]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=3)[CH:25]=2)=[O:19])=[N:16][CH:17]=1>CS(C)=O.CO>[CH3:35][O:34][C:32]1[CH:33]=[C:28]([CH2:27][CH2:26][C:24]2[CH:25]=[C:21]([NH:20][C:18]([C:15]3[CH:14]=[N:13][C:12]([N:7]4[CH2:8][CH2:9][CH2:10][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:17][N:16]=3)=[O:19])[NH:22][N:23]=2)[CH:29]=[C:30]([O:36][CH3:37])[CH:31]=1
Reactant: CC(C)N1CCCNCC1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Solvent: CO
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCCN(C(C)C)CC4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
1-isopropyl-1,4-diazepane (228 mg, 1.60 mmol) was added to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (310 mg, 0.80 mmol) in DMSO (4.00 ml) at 25° C. The resulting solution was stirred at room temperature for 2 hours. The reaction was incomplete so the temperature was increased to 60° C. and the reaction mixture was stirred for a further 2 h. The reaction was still incomplete so the reaction mixture was stirred for a further 18 h at room temperature. The reaction mixture was diluted with MeOH (5 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford crude product as an orange dry film. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (167 mg, 42%) as a pale yellow solid.
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[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30]>>[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[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: O=C(CCl)N1CCOCC1
Product: O=C(Cn1cc(C(=O)N2CCC3(CC2)OCc2ccccc23)c2ccc(Cl)cc21)N1CCOCC1

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (the preparation of which have been described in example 69) with commercially available 2-Chloro-1-morpholin-4-yl-ethanone as electrophile, the title compound was obtained as a white powder.
Reaction SMILES: [Br:1][C:2]1[N:12]=[CH:11][C:10]([CH:13](Br)Br)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].CC[OH:18]>[N+]([O-])([O-])=O.[Ag+].O>[Br:1][C:2]1[N:12]=[CH:11][C:10]([CH:13]=[O:18])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCO
Reactant: CCOC(=O)c1cc(C(Br)Br)cnc1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CCOC(=O)c1cc(C=O)cnc1Br
Yield: 48 %

Procedure:
A mixture of 6 (9.8 g, 0.024 mol), AgNO3 (8.8 g, 0.052 mol), EtOH (100 mL) and H2O (25 mL) was heated on a steam bath for 1 hour. The yellow solid was filtered and the solution concentrated to dryness. The residue was treated with H2O and extracted with CHCl3 (3×). The organic layer was dried, filtered and concentrated to dryness. Distillation of the resulting oil at 105°-135° C. at 0.5 mm gave 3.0 g (48%) of 3; 1H NMR (CDCl3) 1.45 δ (3H, t, J=7), 4.4 (2H, q, J=7, 8.6 (1H, d, J=2),/8.9 (1H, d, J=2) and 10.1 (1H, s).