Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][CH2:28][O:29][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCCOS(C)(=O)=O)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxypentyl)-2,2-dimethyloxazolidine-3-carboxylate (32 g, 74.2 mmol) and Et3N (22.5 g, 226 mmol) in CH2Cl2 (400 mL) was added a solution of MsCl (10.1 g, 89 mmol) in CH2Cl2 (50 mL) at 0-5° C. After addition, the reaction mixture was allowed to warm to rt and stir for 1 hr. The reaction was washed with water (200 mL) and the aqueous layer was extracted with CH2Cl2 (3×150 mL). The combined organic layers was washed with 10% citric acid (60 mL), sat. NaHCO3 (60 mL) and brine (100 mL), then dried over Na2SO4, filtered and concentrated to give (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)-5-(methylsulfonyloxy)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (37.7 g, 100%), which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:19]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:17]
Reactant: CNc1ccc(F)cc1F
Reactant: Cc1ccc2c(c1)-c1sc(C(=O)O)cc1CO2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(F)cc3F)cc1CO2
Reaction time: 24 h

Procedure:
8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid was converted to the acid chloride as in Example 3, then treated with N-methyl-2,4-difluoroaniline (1.5 equiv), and triethylamine (5 equiv) in dichloromethane and N,N-dimethyl-4-aminopyridine (0.2 equiv) at 24° C. After about 24 hr, the reaction mixture was diluted with dichloromethane, and the resulting solution was washed with saturated aqueous sodium bicarbonate. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (5:2 hexanes/ethylacetate) provided 167bp. 1H NMR (500 MHz, CDCl3) δ 7.29 (m, 1 H), 6.95-6.98 (m, 4 H,), 6.78 (d, J=8.2 Hz, 1 H), 5.04 (s, 2 H), 3.39 (s, 3 H), 2.27 (s, 3 H). LCMS (ESI) m/z: 372.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1.Cl[Sn]Cl.CC[OH:18]>>[NH2:10][C:5]1[C:6]([C:8]([NH2:9])=[O:18])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CCO
Agent: Cl[Sn]Cl
Product: NC(=O)c1nc(Cl)ccc1N
Temperature: 90 °C

Procedure:
6-chloro-3-nitro-pyridine-2-carbonitrile (100 mg, 0.54 mmol) is taken up in EtOH (1 mL), combined with SnCl2 (413 mg, 2.18 mmol) and heated to 90° C. for 3 h. Then the solvent is removed, the residue is taken up in ethyl acetate and first of all washed with NaHCO3 to pH 7, then washed with NaOH (2 M) to pH 8-9. Then the residue is filtered through Celite®, the filtrate is extracted again with ethyl acetate and the combined organic phases are dried on Na2SO4. The solvent is eliminated in vacuo and 3-amino-6-chloro-pyridine-2-carboxylic acid amide is obtained (HPLC-MS: tRet.=0.78 min, MS(M+H)+=172, method LCMSBAS1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16]Br.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: O=C1NCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1NCCc2ccc(OCCCBr)cc21
Reaction time: 8 h
Yield: 63.3 %

Procedure:
A mixture of intermediate 19 (326 mg, 2 mmol), 1,3-dibromopropane (0.62 mL, 6 mmol) and anhydrous K2CO3 (276 mg, 2 mmol) was dissolved in 4 mL of EtOH and the solution was heated to reflux and stirred overnight. The mixture was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with water, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=5:1) to give 7-(3-bromopropoxy)-3,4-dihydroisoquinolin-1(2H)-one (intermediate 20) (360 mg, 63%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2OC(=O)[S:10][N:9]=2)=[CH:4][CH:3]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[C:15]#[CH:16]>ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]([C:14]([O:18][CH2:19][CH3:20])=[O:17])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#CC(=O)OCC
Reactant: O=c1oc(-c2ccc(F)cc2)ns1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)ns1
Temperature: 135 °C
Yield: 31.8 %

Procedure:
To a stirred solution of 5-(4-fluorophenyl)-1,3,4-oxathiazol-2-one (42.80 g, 217.1 mmol) in o-dichlorobenzene (600 mL) was added ethyl propiolate (66.0 mL, 651 mmol). The mixture was heated overnight at 135° C. and concentrated. The residual oil was purified by flash chromatography using a hexane/ethyl acetate gradient to afford ethyl 3-(4-fluorophenyl)isothiazole-5-carboxylate as a pale golden solid (17.35 g, 32%). The more polar, ethyl 3-(4-fluorophenyl)isothiazole-4-carboxylate isomer (generated in ˜57/43 ratio versus the desired product) was discarded.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=2)[C:4]([C:15]2[N:20]=[C:19]3[C:21]([C:32]([O:34]C)=[O:33])=[CH:22][N:23](COC(=O)C(C)(C)C)[C:18]3=[N:17][CH:16]=2)=[N:3]1.[OH-].[Na+]>O1CCOCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:13])([F:14])[F:12])=[CH:8][CH:9]=2)[C:4]([C:15]2[N:20]=[C:19]3[C:21]([C:32]([OH:34])=[O:33])=[CH:22][NH:23][C:18]3=[N:17][CH:16]=2)=[N:3]1
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4ccc(C(F)(F)F)cc34)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2cc(C(F)(F)F)ccc21
Temperature: 90 °C
Reaction time: 7 h
Yield: 110.7 %

Procedure:
To a suspension of methyl 2-(1-methyl-5-(trifluoromethyl)-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (50 mg, 0.1 mmol) in dioxane/water (4 mL/4 mL) was added NaOH (40 mg, 1.0 mmol), the reaction mixture was heated to 90° C. with stirring for 7 hours, the dioxane was removed under reduced pressure, the aqueous layer was adjusted to pH=3 with 1 N HCl, the precipitate was collected by filtration and washed with water (5 mL) and dried to afford 2-(1-methyl-5-(trifluoromethyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (40 mg, crude) as an orange solid. LCMS: (M+H)+=362.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([C:11]([OH:13])=O)[CH2:9][CH2:8][N:7]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:6]1)=[O:4].CN(C)C=O.Cl.Cl.[CH3:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[C:35]#[N:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[C:35]([C:34]1[CH:37]=[CH:38][C:39]([N:40]2[CH2:45][CH2:44][N:43]([C:11]([C@H:10]3[CH2:9][CH2:8][N:7]([C:14]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:15])[CH2:6][C@@H:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:13])[CH2:42][CH2:41]2)=[C:32]([CH3:31])[CH:33]=1)#[N:36]
Reactant: COC(=O)[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1C(=O)O
Reactant: Cc1cc(C#N)ccc1N1CCNCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of (3R,4S)-piperidine-1,3,4-tricarboxylic acid 1-benzyl ester 3-methyl ester (0.554 g, 0.00172 mol) in N,N-dimethylformamide (8.500 mL, 0.1098 mol) was added 3-methyl-4-piperazin-1-ylbenzonitrile dihydrochloride (0.6146 g, 0.002241 mol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.017 g, 0.001896 mol), and, N,N-diisopropylethylamine (1.509 mL, 0.008620 mol). The reaction mixture was stirred overnight at room temp. Reaction quenched with KH2PO4 (sat solution). Layers separated and aq layer extracted with ethyl acetate 3×. Organic layers were washed with brine and dried over magnesium sulfate. Filtered and concentrated. The residue was purified by Combiflash with 40-70% EtOAc/Hex to give the product (75% in yield). MS (ESI): (M+H)+=505.
Reaction SMILES: [O:1]=[C:2]=[N:3][C@H:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]([CH3:7])[CH3:6].[CH3:12][C:13]([NH2:19])([CH2:15][CH2:16][CH:17]=[CH2:18])[CH3:14]>C1COCC1>[CH3:12][C:13]([NH:19][C:2]([NH:3][C@H:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]([CH3:6])[CH3:7])=[O:1])([CH3:14])[CH2:15][CH2:16][CH:17]=[CH2:18]
Reactant: COC(=O)[C@@H](N=C=O)C(C)C
Reactant: C=CCCC(C)(C)N
Solvent: C1CCOC1
Product: C=CCCC(C)(C)NC(=O)N[C@H](C(=O)OC)C(C)C
Reaction time: 0.08 h

Procedure:
Methyl N-(oxomethylene)-L-valinate (2.80 g, 17.7 mmol) was added to 2-methylhex-5-en-2-amine [J. Org. Chem. (1976) 41(5) 855-863.] (2.00 g, 17.7 mmol) in THF (15 mL). After 5 minutes, the reaction mixture was evaporated to give the title compound as a solid, which was triturated with hexane and isolated by filtration (2.71 g). LRMS (M+H)+=271.4.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6](/[CH:13]=[CH:14]/[C:15]([O:17]C)=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[OH-].[K+].O>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(/C=C/C(=O)OC)cc1OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1ccc(/C=C/C(=O)O)cc1OCC
Temperature: 70 °C

Procedure:
1.0 g (4.00 mmol) of methyl 3(E)-(3,4-diethoxyphenyl)acrylate is suspended in 30 ml of a 10% solution of potassium hydroxide in methanol. Thereafter, 2 ml of water are added and the mixture is heated to 70° C. for 3 hours. The reaction mixture is then cooled and is partitioned between diethyl ether and water, the organic phase is washed several times with saturated sodium chloride solution and the combined aqueous phases are adjusted to pH 4 with a 25% hydrochloric acid solution and are extracted several times with methylene chloride. The methylene chloride phases are combined, dried over magnesium sulfate, filtered and evaporated down. This gives 3(E)-(3,4-diethoxyphenyl)acrylic acid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][CH:13]=[C:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[N:14]([CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:13]=[C:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1ccccc1C1=CNC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: ClCCN1CCCC1
Product: Cc1ccccc1C1=CN(CCN2CCCC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=580.1 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8-diaza-spiro[4.5]dec-3-en-1-one and 1-(2-chloroethyl)-pyrrolidine.
Reaction SMILES: C(O)C.C([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C:22]([CH2:31][CH3:32])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[O:23]2)=[CH:18][CH:17]=1)C1C=CC=CC=1>[Pd].O>[OH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C:22]([CH2:31][CH3:32])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[O:23]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1(CC)CCc2ccc(OCCCOCc3ccccc3)cc2O1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(CC)CCc2ccc(OCCCO)cc2O1
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To an 80 ml ethanol solution of ethyl 7-(3-benzyloxypropoxy)-2-ethylchromane-2-carboxylate (3.76 g, 9.5 mmol) was added water 4 ml and 10% Pd/C 300 mg. This solution was placed in a Parr shaker and was shaken under hydrogen atmosphere (50 psi) overnight. The catalyst was removed by filtration through a pad of celite. The filtrate was concentrated and chromatographed on silica gel. Elution with 30% AcOEt/hexanes gave the title compound 2.88 g as colorless syrup (quant.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:8][CH2:9][CH2:10][CH2:11][N:12](CC1C=CC=CC=1)[CH2:13][C@H:14]([OH:18])[CH2:15][C:16]#[N:17])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.O=[Pt]=O>[C:6]([OH:34])(=[O:5])[CH3:7].[C:6]([OH:34])(=[O:5])[CH3:7].[C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C@H:14]([OH:18])[CH2:15][CH2:16][NH2:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN(Cc1ccccc1)C[C@H](O)CC#N)C(=O)OC(C)(C)C
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC[C@H](O)CCN)C(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 280.6 %

Procedure:
The Nε benzyl nitrile (6) (4.80 g, 10.7 mmol) was dissolved in glacial acetic acid (100 ml); 10% Pd--C (0.50 g) and PtO2 (1.00 g) were added; and hydrogen gas was introduced. The reaction was complete after 6 hours, and the catalyst was filtered through a bed of Celite and washed with acetic acid. The filtrate was concentrated in vacuo. Azeotropic removal of the acetic acid with toluene gave (7) as a colorless oil (5.10 g, 99%) 1H NMR (500 MHz) (CD3OD) δ4.02-3.94 (m, 2H), 3.14-2.86 (m, 6H), 1.94 (s, 6H), 1.87-1.58 (m, 8H), 1.46 (s, 9H), 1.44 (s, 9H). 13C NMR (CD3OD) δ169.6, 156.54, 85.3, 70.2, 62.6, 56.6, 54.2, 53.9, 34.0, 31.1, 28.2, 26.3, 23.2. HRMS m/z calcd. for C19H40N3O5 390.2968, found 390.2977. [α]25D +0.6° (c=1.00, CH3OH).
Reaction SMILES: [Na].[CH2:2]1[O:12][C:11]2[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][C:4]=2[O:3]1.[Br:13][CH2:14][C:15]([CH3:19])=[CH:16][CH2:17]Br>COCCOC>[Br:13][CH2:14][C:15]([CH3:19])=[CH:16][CH2:17][O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:11]2[O:12][CH2:2][O:3][C:4]=2[CH:5]=1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: CC(=CCBr)CBr
Agent: [Na]
Solvent: COCCOC
Product: CC(=CCOCc1ccc2c(c1)OCO2)CBr
Reaction time: 0.25 h

Procedure:
8.7 g (0.05 mol) of sodium salt of the 3,4-methylendioxybenzylalcohol are added at 0° during the course of 15 minutes and while stirring to 12.5 g (0.055 mol) of 1,4-dibromo-2-methyl-2-butene which is dissolved in 100 cc of 1,2-dimethoxyethane. The mixture is stirred at 20°-25° for 16 hours and at 50° for 15 minutes. The solvent is then distilled off at reduced pressure and 100 cc amounts of water and ether are added to the residue. The aqueous phase is separated in a separatory funnel, the ether phase is extracted with saturated salt solution, is dried with sodium sulphate and evaporated. The residue is chromatographed on silica gel with hexane/ethyl acetate 9 : 1, whereby the 5-[(4-bromo-3-methyl-2-butenyloxy)-methyl]-1,3-benzodioxol is obtained as uniform colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:39])[C:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[C:28]([C:33]2[CH2:37][CH2:36][CH2:35][C:34]=2Br)[CH:27]=1)[CH3:23]>>[CH2:22]([O:24][C:25](=[O:39])[C:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[C:28]([C:33]2[CH2:37][CH2:36][CH2:35][C:34]=2[C:10]2[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:27]=1)[CH3:23]
Reactant: CCOC(=O)c1cc(C2=C(Br)CCC2)ccc1N
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Product: CCOC(=O)c1cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)ccc1N

Procedure:
Prepared by general procedure C(iii) but using 2-benzyloxy-5-trifluoromethylphenylboronic acid instead of 2-benzyloxy-5-chlorophenylboronic acid and 3-(2-bromocyclopent-1-enyl)-6-aminobenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methylbenzoic acid ethyl ester.
Reaction SMILES: [C:1]([NH2:4])(=O)[CH3:2].O=P(Cl)(Cl)Cl.[BH4-].[Na+].[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[CH2:18]1[C:12]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:2][CH2:1][NH:4]1
Reactant: CC(N)=O
Reactant: Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: c1ccc2c(c1)CCNC2
Yield: 51 %

Procedure:
Primary amine from example 1 (200 mg) was reacted with acetyl chloride (1.3 eq.) in dry ethylamine (3 eq.) and dry dichloromethane (5 ml) at 0° C. for 1 hour, then 25° C. for 14 hours and gave the acetamide in 88% yield. The acetamide (103 mg, 0.263 mmol) was refluxed for 3 hours with POCl3 (7.5 eq.) in dry toluene (10 ml) at 110° C. for 14 hours followed by NaBH4 reduction (11 eq.) in dry ethanol gave the corresponding 1,2,3,4-tetrahydroisoquinoline (50 mg, 51%). Demethylation as in example 1 gave the expected product as the hydrobromide salt (50 mg, 87%).
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][C:33](O)=[O:34])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][C:33]([N:18]2[CH2:19][CH2:20][CH:15]([C:12]3[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:11]=3)[CH2:16][CH2:17]2)=[O:34])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(CCC(=O)O)cc1OC
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Agent: Cl
Product: COc1ccc(CCC(=O)N2CCC(c3nc(CCc4ccccc4)cs3)CC2)cc1OC

Procedure:
4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 309 mg) is reacted analogously to Example I-63 with 3-(3,4-dimethoxyphenyl)propanoic acid (231 mg). After chromatographic purification, this gives 3-(3,4-dimethoxyphenyl)-1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}propan-1-one (139 mg).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:4]2[N:3]1[CH2:15][C:16]([OH:18])=O.[Br:19][C:20]1[C:21]([C:26]2[NH:30][N:29]=[CH:28][N:27]=2)=[C:22]([NH2:25])[S:23][CH:24]=1>>[Br:19][C:20]1[C:21]([C:26]2[NH:30][N:29]=[CH:28][N:27]=2)=[C:22]([NH:25][C:16](=[O:18])[CH2:15][N:3]2[C:2](=[O:1])[CH:7]=[CH:6][N:5]3[N:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=[C:4]23)[S:23][CH:24]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cn1c(=O)ccn2nc(C(F)(F)F)cc12
Product: O=C(Cn1c(=O)ccn2nc(C(F)(F)F)cc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(5-oxo-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetic acid (63 mg, 0.244 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (30 mg, 0.122 mmol) according to protocol A. Retention time (min)=4.975, method [7], MS (ESI) 488.0 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.79 (d, J=7.4 Hz, 1H), 8.61 (bs, 1H), 7.32 (s, 1H), 6.96 (s, 1H), 6.45 (d, J=7.4 Hz, 1H), 5.01 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>N1C=CC=CC=1>[O:21]=[C:13]1[N:12]2[CH2:22][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=4)=[CH:3][CH:4]=3)[CH2:9][N:10]=[C:11]2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:14]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.9 %

Procedure:
To a solution of 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (10.8 mg, 0.037 mmol) in 0.7 mL pyridine at rt was added 3-(trifluoromethyl)benzoyl chloride (0.0066 mL, 0.044 mmol) and the reaction stirred at rt. After 5 min, the reaction was briefly warmed to dissolve solids and then allowed to cool to rt. At 45 min an additional amount (pipet tip) of 3-(trifluoromethyl)benzoyl chloride was added, the reaction briefly warmed, and then allowed to stir at rt overnight. At 24 hours the reaction was quenched with MeOH and evaporated. The crude mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with brine, dried with Na2SO4, and evaporated. The resulting solid was triturated with hot EtOAc, hexane added, the solid filtered and rinsed with 30% EtOAc/hexane to give the title compound as an off-white solid (10.3 mg, 60%). 1H NMR (CD3OD/CDCl3 mixture) δ: 8.25 (s, 1H), 8.18 (d, J=7.6 Hz, 1H), 8.02 (dd, J=8.1, 1.3 Hz, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.65-7.75 (m, 3H), 7.43-7.50 (m, 1H), 7.29-7.35 (m, 2H), 7.10-7.17 (m, 1H), 7.00-7.05 (m, 1H), 4.39-4.47 (m, 1H), 3.81-3.90 (m, 1H), 3.61-3.72 (m, 2H), 3.07-3.18 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[CH3:48][C:49]12[CH2:56][CH:53]([NH:54][CH2:55]1)[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50]2>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:54]2[CH2:55][C:49]3([CH3:48])[CH2:56][CH:53]2[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50]3)=[O:15])=[CH:16][CH:17]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Reactant: CC1(C)CC2CC(C)(CN2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)C1
Reaction time: 0.17 h
Yield: 77.3 %

Procedure:
To a mixture of 4-tert-butoxycarbonylamino-benzoic acid (50 g, 0.21 mol) and HOBT (31.33 g, 0.231 mol) in dry THF (0.5 L) was added EDAC (44.44 g, 0.231 mol). The resulting mixture was stirred for 10 min followed by addition of a mixture of DIPEA (40.4 ml, 0.231 mol) and 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (39.4 ml, 0.231 mol). The reaction mixture was stirred for an additional 16 hrs. and evaporated to dryness. To the residue was added water (600 ml) and the resulting mixture was extracted with EtOAc (3×500 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel) using a mixture of EtOAc-Heptane (1:2) as eluent. Pure fractions were collected and evaporated to dryness. To the solid residue was added diethyl ether (100 ml) and the precipitate was filtered off, washed with diethyl ether and dried in vacuo at 50° C. affording 60.5 g (77%) of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]carbamic acid tert-butyl ester as a solid.