Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+:19]>C(O)C>[Na+:19].[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([O-:16])=[O:15])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(=O)CCCC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1ccc(C(=O)CCCC(=O)[O-])cc1
Reaction time: 8 h

Procedure:
Compound 11 was prepared as follows. 5-(4-Isopropyl-phenyl)-5-oxo-pentanoic acid (5 g, 21.3 mmol) was dissolved in 75 mL ethanol in a 250 mL flask. Sodium hydroxide (0.85 g, 21.3 mmol) was added and the reaction stirred overnight under reduced pressure on a rotary evaporator. The solid was dried under vacuum and used without further purification. Found: C, 60.24, H, 6.66, Na, 9.21%; C14H17O3Na requires C, 61.28; H, 6.98, Na, 8.38%. 1H NMR (D2O): δ 7.7, d, 2H (aryl-H's); δ 7.2 d, 2H (aryl H's); δ 2.9, t, 2H(CH2 α to carbonyl); δ 2.8, multiplet, 1H, (CH of isopropyl group); δ 2.1, t, 2H (CH2 α to COOH); δ 1.8, q, 2H (CH2 β to both carbonyl & COOH), δ 1.1, d, 6H (CH3's of isopropyl group).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[Br:19]N1C(=O)CCC1=O>>[Br:19][C:7]1[CH:6]=[C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: CCCS(=O)(=O)c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: CCCS(=O)(=O)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 1-fluoro-4-(propylsulfonyl)benzene (Intermediate 105; 1.00 g; 4.94 mmol) in conc. sulfuric acid (3.97 ml; 74.2 mmol) was treated with N-bromosuccinimide (968 mg; 5.44 mmol) and stirred at RT for 6 hours. The reaction mixture was carefully poured on crushed ice, extracted with AcOEt and the organic phase was washed with a 0.1 N solution of NaOH in water twice, then with brine twice. The organic phase was dried on MgSO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][NH2:12])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[CH2:24][C:25]1[N:29]2[N:30]=[C:31]([C:34](=O)[CH3:35])[CH:32]=[CH:33][C:28]2=[N:27][CH:26]=1>>[CH2:1]([NH:8][C:9]([NH:11]/[N:12]=[C:34](/[C:31]1[CH:32]=[CH:33][C:28]2[N:29]([C:25]([CH2:24][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][C:14]=3[F:13])[N:21]=[CH:20][CH:19]=[CH:18]4)=[CH:26][N:27]=2)[N:30]=1)\[CH3:35])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=S)NCc1ccccc1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Product: C/C(=N\NC(=S)NCc1ccccc1)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 80 %

Procedure:
The title compound was prepared from N-benzylhydrazine carbothioamide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 80% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.58 (s, 1H), 9.30 (t, 1H), 8.86 (dd, 1H), 8.30 (m, 2H), 8.05 (d, 1H), 7.95 (d, 1H), 7.77 (d, 1H), 7.69 (s, 1H), 7.47 (q, 1H), 7.32 (m, 4H), 7.23 (m, 1H), 4.89 (d, 2H), 4.58 (s, 2H), 2.39 (s, 3H). LCMS (method C): [MH]+=484, tR=4.18 min.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][CH:24]2[CH2:26][CH2:25]2)=[C:8]([C:10]2[C:11]3[NH:18][CH:17]=[C:16]([C:19]([OH:21])=O)[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:9]=1)(=[O:3])[CH3:2].[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34](=[O:38])[CH2:35][O:36][CH3:37])[CH2:30][CH2:29]1>>[CH3:37][O:36][CH2:35][C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:19]([C:16]2[C:12]3[N:13]=[CH:14][N:15]=[C:10]([C:8]4[CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=4[O:22][CH2:23][CH:24]4[CH2:26][CH2:25]4)[C:11]=3[NH:18][CH:17]=2)=[O:21])[CH2:33][CH2:32]1)=[O:38]
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)c1
Reactant: COCC(=O)N1CCC(N)CC1
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(C(C)=O)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(5-acetyl-2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A81) and 1-(4-amino-piperidin-1-yl)-2-methoxy-ethanone (A192) the title compound is obtained as colorless solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:20]([O:22][C:23](=[O:27])[CH2:24][CH2:25]Cl)[CH3:21].O>CN(C)C=O>[CH2:20]([O:22][C:23]([CH:24]([C:15]1[NH:16][C:17]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[CH:19][CH:18]=2)[CH3:25])=[O:27])[CH3:21]
Reactant: CCOC(=O)CCCl
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 60% sodium hydride (15 g) in dimethylformamide (30 ml) was added a N,N-dimethylformamide solution of 5-benzyloxyindole (5.0 g) at 0° C. After 15 minutes a solution of ethyl-3-chloropropionate (3.1 ml) in N,N-dimethylformamide was added dropwise and the reaction mixture stirred for a further 5 hours at ambient temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 15%-ethyl acetate in n-hexanes to yield the title product (6.81 g).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[N:18]1([CH2:17][CH2:16][O:15][C@H:12]2[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](OCCN3CCCCC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: N[C@H]1CC[C@H](OCCN2CCCCC2)CC1

Procedure:
Trans-N,N-dibenzyl-4-(2-(piperidin-1-yl)ethoxy)cyclohexanamine (4.7 g, 11.6 mmol), 20% Pd(OH)2/C (0.94 g) and methanol (40 mL) were charged into a septum-sealed flask. The reaction mixture was placed under balloon pressure of hydrogen for 18 h at ambient temperature, at which time LCMS indicated complete debenzylation to form the free amine. The catalyst was filtered off and the filtrate evaporated under reduced pressure to give 2.42 g of a crystalline material (93%). In some cases an additional portion of catalyst (ca. 50% of the initial charge) was needed in order to attain complete reaction. LRMS (ES) m/e 227.2 [MH]+; 1H NMR (300 MHz, CD3OD) δ 3.51 (t, 2H), 3.12 (m, 1H), 2.61 (m, 1H), 2.42 (t, 2H), 2.18 (m, 4H), 1.93 (m, 2H), 1.80 (m, 2H), 1.50 (m, 4H), 1.33 (m, 2H), 1.12 (m, 4H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37]C)[CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30]C)=[C:26]([O:32]C)[CH:25]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:32][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[OH:30])[CH2:23][C@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:7]1[CH2:6][C:5]1[CH:34]=[CH:35][C:36]([OH:37])=[C:3]([OH:2])[CH:4]=1
Reactant: COc1ccc(C[C@H]2CCCN2CCCCCCN2CCC[C@@H]2Cc2ccc(OC)c(OC)c2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc(C[C@H]2CCCN2CCCCCCN2CCC[C@@H]2Cc2ccc(O)c(O)c2)cc1O
Temperature: 25 °C

Procedure:
To a solution of (R,R)-1,6-bis-[2-(3,4-dimethoxybenzyl)pyrrolidin-1-yl]hexane (0.001 mol) in dry CH2Cl2 at -70° C. under an inert atmosphere was added BBr3 (4 mL of a 1M solution, 0.004 mol). The reaction mixture was warmed to room temperature, recooled to -70° C., and CH3OH (4 mL) was added. After warming to room temperature, the solvent was removed in vacuo. The residue was subjected to column chromatography, eluting with CH3OH. The fractions containing the desired product were concentrated in vacuo to provide (R,R)-1,6-bis[2-(3,4-dihydroxybenzyl)pyrrolidin-1-yl]hexane, [α]D25 =12.86°.
Reaction SMILES: [CH:1]([NH:3][NH2:4])=[O:2].[F:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[CH2:8][N:9]=[C:10]=[O:11]>C1COCC1>[F:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[CH2:8][NH:9][C:10]([NH:4][NH:3][CH:1]=[O:2])=[O:11]
Reactant: O=C=NCc1ccccc1F
Reactant: NNC=O
Solvent: C1CCOC1
Product: O=CNNC(=O)NCc1ccccc1F
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Under argon, 1.99 g (33 mmol) of formylhydrazine are placed in 80 ml THF. The solution is heated to 50° C., treated dropwise with a solution of 5.00 g (33 mmol) of 2-fluorobenzyl isocyanate in 50 ml THF and the resulting mixture stirred for 30 mins more at 50° C. It is then freed of solvent on the rotary evaporator. The residue is stirred with diethyl ether, the precipitate suction-filtered, then washed with diethyl ether and the white solid dried under high vacuum. 5.73 g (82% of theory) of the target product are obtained.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:13])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH:6]=[CH:5][NH:4]1.[CH3:14]I.[NH4+].[Cl-]>CN(C=O)C.C(OCC)(=O)C>[CH3:14][N:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]1=[O:13]
Reactant: O=c1[nH]ccc2ccncc12
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc2ccncc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
Sodium hydride (2.9 g, 72.5 mmol, 60% in oil) was added in portions to 2H-2,7-naphthyridin-1-one (3.5 g, 24.0 mmol) in dry DMF (50 mL) at 0° C. After stirring at 0° C. for 30 min, MeI (17.0 g, 118.7 mmol) was added and the mixture was stirred for an additional 30 min. Saturated aqueous NH4Cl (250 mL) and ethyl acetate (100 mL) were added. Extractive work up with ethyl acetate and purification by silica gel chromatography (DCM:MeOH=100:1 to 10:1) gave the title compound (0.5 g, 13.1%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 9.54 (1H, s), 8.64-8.62 (1H, d, J=5.6 Hz), 7.27-7.26 (1H, d, J=5.2 Hz), 7.22-7.20 (1H, d, J=5.6 Hz), 6.37-6.35 (1H, d, J=7.2 Hz), 3.54 (3H, s).
Reaction SMILES: [CH:1]1([C:4]2[O:8][C:7]([CH2:9][O:10][CH3:11])=[N:6][C:5]=2[CH2:12][C:13]([O:15]CC)=[O:14])[CH2:3][CH2:2]1.Cl>[OH-].[K+]>[CH:1]1([C:4]2[O:8][C:7]([CH2:9][O:10][CH3:11])=[N:6][C:5]=2[CH2:12][C:13]([OH:15])=[O:14])[CH2:2][CH2:3]1
Reactant: CCOC(=O)Cc1nc(COC)oc1C1CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COCc1nc(CC(=O)O)c(C2CC2)o1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl [5-cyclopropyl-2-(methoxymethyl)-1,3-oxazol-4-yl]acetate (Preparation 120, 23.9 g, 0.1 mol) in 10% KOH (100 mL) was stirred at 75° C. for 18 hours. The reaction was cooled and acidified with 10% HCl to pH 3, and extracted with chloroform (3×100 mL). The organic extract was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in ether and crystallized in a refrigerator at −20° C. The precipitated crystals were separated by filtration, washed with cold ether, and vacuum-dried to give the title compound as a white crystalline substance in a form of light plates (16.9 g, 93.2%).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([CH3:21])[CH:15]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([NH:8][C:9](=[O:12])[CH2:10][NH:18][C:17]1[CH:19]=[CH:20][C:14]([F:13])=[CH:15][C:16]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(F)ccc1N
Reactant: O=C(CCl)NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1NCC(=O)NCc1ccccc1
Temperature: 100 °C

Procedure:
To a solution of N-benzyl-2-chloro-acetamide (20 g) in DMF (200 mL) were added 4-fluoro-2-methylaniline (13.3 mL) and N,N-diisopropylethylamine (22.2 mL). The reaction mixture was heated to 100° C. over night, cooled to room temperature, and the mixture was diluted with ethyl acetate and washed with water. The combined inorganic phases were extracted with ethyl acetate and the combined organic phases were dried (Na2SO4), filtered and evaporated. The crude product was purified by chromatography (SiO2, n-heptane/ethyl acetate 1:2) to give N-benzyl-2-(4-fluoro-2-methyl-phenylamino)-acetamide (20 g) as grey solid, MS: 273.0 ([M+H]+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]3[CH2:35][CH2:34][CH:33]([N:36]([CH2:41][CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[S:37]([CH3:40])(=[O:39])=[O:38])[CH2:32][CH2:31]3)[N:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)C(F)(F)F>[C:47]([Si:44]([CH3:46])([CH3:45])[O:43][CH2:42][CH2:41][N:36]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:33]1[CH2:34][CH2:35][CH:30]([NH:29][C:25]2[N:24]=[C:23]([N:18]3[C:19]4[C:15](=[C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:22]=[CH:21][CH:20]=4)[CH:16]=[CH:17]3)[CH:28]=[CH:27][N:26]=2)[CH2:31][CH2:32]1)([CH3:48])([CH3:50])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2ccn3-c2ccnc(NC3CCC(N(CCO[Si](C)(C)C(C)(C)C)S(C)(=O)=O)CC3)n2)CC1
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)OCCN(C1CCC(Nc2nccc(-n3ccc4c(N5CCNCC5)cccc43)n2)CC1)S(C)(=O)=O
Temperature: 150 °C
Yield: 123.3 %

Procedure:
4-{1-[2-(4-{[2-(t-Butyl-dimethyl-silanyloxy)-ethyl]-methanesulfonylamino}-cyclo-hexylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-piperazin-1-carboxylic acid t-butyl ester (0.251 g, 0.345 mmol) and hexafluoroisopropanol (10 mL) were combined and heated to 150° C. for 2 h in a microwave oven. The solvent was removed in vacuo to yield crude 1-{1-[2-(4-{[2-(t-Butyl-dimethyl-silanyloxy)-ethyl]-methanesulfonylamino}-cyclohexylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-piperazine (0.267 g). This intermediate (0.193 g) and acetic anhydride (0.03 mL) in NMP (0.3 mL) was allowed to stir at RT for 6 h. EtOAc and water were then added, the organic layer separated and the organic layers combined, washed with water, sat. NaHCO3, dried over sodium sulfate, filtered, the solvent removed in vacuo, and the product purified on a silica column eluting with 0% to 10% MeOH/EtOAc to yield 1-{1-[2-(4-{[2-(t-butyl-dimethyl-silanyloxy)-ethyl]-methanesulfonylamino}-cyclohexylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-4-acetyl-piperazine (0.119 g, 58%).
Reaction SMILES: C([O:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C.[CH3:13][C:14]1([O:22][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[CH2:28])=[CH:25][CH:24]=2)[CH2:19][CH2:18][Si:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[CH3:13][C:14]1([O:22][C:23]2[CH:24]=[CH:25][C:26]([CH:27]=[CH2:28])=[CH:29][CH:30]=2)[CH2:19][CH2:18][Si:17]([CH3:20])([CH3:21])[CH2:16][CH2:15]1.[OH:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)OC=Cc1ccccc1
Agent: C=Cc1ccc(OC2(C)CC[Si](C)(C)CC2)cc1
Solvent: Cc1ccccc1
Product: OC=Cc1ccccc1
Temperature: 60 °C

Procedure:
In a 2-liter flask, 30 g of p-(1,4,4-trimethyl-4-silacyclohexyloxy)styrene and 45 g of acetoxystyrene were dissolved in 560 ml of toluene. After thorough purging of oxygen from the system, 5.5 g of an initiator AIBN was added to the system, which was heated at 60° C. whereupon polymerization reaction took place for 24 hours. A similar subsequent procedure yielded a p-(1,4,4-trimethyl-4-silacyclohexyloxy)styrene/hydroxystyrene (3:7) copolymer. This polymer was transferred to a 3-liter flask where it was dissolved in 500 g of methanol and 400 g of acetone. 97 g of triethylamine and 50 g of pure water were added to the solution, which was heated at 60° C. whereupon hydrolysis reaction took place for 20 hours.
Reaction SMILES: Cl.[CH:2]([C:4]1[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1)=O.[F:13][C:14]([F:18])([F:17])[CH2:15][NH2:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:13][C:14]([F:18])([F:17])[CH2:15][NH:16][CH2:2][C:4]1[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1
Reactant: NCC(F)(F)F
Reactant: O=Cc1cccc(B(O)O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: OB(O)c1cccc(CNCC(F)(F)F)c1
Reaction time: 72 h
Yield: 36.3 %

Procedure:
Dissolve 3-formylphenyl boronic acid hydrochloride (2.5 g, 16.67 mmol) and 2,2,2,-trifluoroethylamine (2.97 g, 30.01 mmol) in DCM (100 mL). Add sodium triacetoxyborohydride (10.6 g, 50.02 mmol) portionwise over 10 min and stir the resulting solution for 72 h. Then quench with water (50 mw). Dry the organic fraction over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with dichloromethane:methanol (1:0 to 19:1) to give the title compound as a colourless oil (1.41 g, 36%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][C@@H:23]([NH:25][C:26]([C:28]3[N:29]=[C:30]([CH2:33]Cl)[O:31][CH:32]=3)=[O:27])[CH3:24])[N:18]=2)[CH:12]=[CH:13][C:14]=1[C:15]#[N:16]>CN(C=O)C>[N:3]1([CH2:33][C:30]2[O:31][CH:32]=[C:28]([C:26]([NH:25][CH:23]([CH3:24])[CH2:22][N:19]3[CH:20]=[CH:21][C:17]([C:11]4[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[C:9]([Cl:8])[CH:10]=4)=[N:18]3)=[O:27])[N:29]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(CCl)n1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(Cn2ccnc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 8.23 %

Procedure:
Sodium hydride (11.87 mg, 0.297 mmol) was added into a flask under nitrogen atmosphere. The flask was cooled to 0° C. and DMF was added through a septum. Imidazole (13.47 mg, 0.198 mmol) was added and the mixture was stirred for 60 min in RT. The mixture was again cooled to 0° C. and (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(chloromethyl)oxazole-4-carboxamide (80 mg, 0.198 mmol) in DMF was added dropwise. The reaction mixture was stirred overnight in RT. DMF was evaporated and the resulting crude product was dissolved in DCM, washed with brine and evaporated. The product was triturated using diethyl ether and purified by Flash-chromatography. Yield 8.23%. 1H-NMR (400 MHz; CDCl3): δ 1.24 (d, 3H), 4.29 (dd, 1H), 4.41 (dd, 1H), 4.58 (m, 1H), 5.26 (s, 2H), 6.64 (d, 1H), 7.00 (t, 1H), 7.11 (t, 1H), 7.49 (d, 1H), 7.60 (s, 1H), 7.61 (d, 1H), 7.68 (d, 1H), 7.78 (dd, 1H), 8.08 (d, 1H), 8.17 (s, 1H).
Reaction SMILES: C1COCC1.C(O)C.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=1[CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].[Cl-].[NH4+]>C(OCC)(=O)C.[Cl-].[Na+].O.[Zn]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH3:9])=[C:11]([CH2:19][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH:12]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1CC(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(N)cc1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a solution of THF:ethanol (1:1, 100 mL) was placed the crude benzyl 2-(2-methyl-5-nitrophenyl)acetate (2.46 g, 8.62 mmol) and ammonium chloride (4.61 g, 86.2 mmol). To this was added zinc dust (5.64 g, 86.2 mmol) and the resulting slurry was stirred at RT for 4 hrs. The slurry was filtered through Celite and washed with ethanol (2×50 mL). The combined filtrates were evaporated at reduced pressure to give an oily mass. This was dissolved in a mixture of ethyl acetate (75 mL) and brine (75 mL). The organic phase dried (Na2SO4) and evaporated at reduced pressure to give benzyl 2-(5-amino-2-methylphenyl)acetate as an oil, which appears to be 6:4 mix of product:non-homologated compound. Used as is.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH:14]([CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1)([CH3:16])[CH3:15]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:18]3[CH2:19][CH2:20][C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]3[CH:14]([CH3:16])[CH3:15])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC(C)C1NCCc2ccccc21
Product: CC(C)C1c2ccccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Isopropyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C([O:3][C:4](=[O:17])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)C.[OH-].[Na+].Cl>C1COCC1.CCO>[F:15][C:13]([F:14])([F:16])[C:10]1[N:9]=[CH:8][C:7](/[CH:6]=[CH:5]/[C:4]([OH:17])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)/C=C/c1ccc(C(F)(F)F)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.7 %

Procedure:
To a solution of (E)-ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)acrylate (2.65 g, 10.8 mmol) in THF/EtOH (1/1, 20 mL) was added 2.28 M NaOH (aq.) (14.2 mL) at rt. The reaction mixture was stirred at rt for 4 h and was then neutralized by adding 1M HCl(aq.). The water-phase was extracted with CH2Cl2/MeOH 9/1 (5×20 mL), the combined organics dried (MgSO4), filtered and evaporated to give the title compound (2.15 g, 9.90 mmol, 91%) as an off white solid. This material was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:21]1[C:30]2[C:25](=[CH:26][C:27]([CH2:31][NH2:32])=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:32][CH2:31][C:27]4[CH:26]=[C:25]5[C:30](=[CH:29][CH:28]=4)[N:21]=[CH:22][CH:23]=[N:24]5)[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: NCc1ccc2nccnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NCc4ccc5nccnc5c4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (100 mg, 0.35 mmol) and quinoxalin-6-ylmethanamine (150 mg, 0.94 mmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (500 μL, 3 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (30-60% acetonitrile-water [10 mM DEA]) to afford a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][CH2:16][C@@H:15](O)[CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:9]2.[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C(N(CC)CC)C>C1COCC1>[F:27][C@H:15]1[CH2:16][CH2:17][C@:8]2([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:9]=[C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:11][CH2:12][C@@H:13]2[CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CC[C@@H](O)C[C@H]2CS1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CC[C@H](F)C[C@H]2CS1
Reaction time: 15 h

Procedure:
tert-Butyl (±)-[(4aR*,6R*,8aS*)-8a-(2-fluorophenyl)-6-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in Preparation Example 64-(4) (500 mg) was dissolved in THF. Then, perfluorobutanesulfonyl fluoride (0.43 mL, specific gravity: 1.682 g/cm3), a triethylamine-trihydrofluoric acid complex (0.39 mL, specific gravity: 0.989 g/cm3) and triethylamine (0.99 mL, specific gravity: 0.73 g/cm3) were sequentially added at room temperature. After completion of the addition, the mixture was stirred for 15 hours. The reaction solution was concentrated under reduced pressure and then the residue was purified by silica gel column chromatography to obtain the title compound (351 mg).