Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[Li]C.C(=O)=O.CC(C)=O.[Cl:17][C:18]1[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([C:28](=[O:30])[CH3:29])=[CH:20][N:19]=1>CCOCC.Cl[Ti](Cl)(Cl)Cl>[Cl:17][C:18]1[N:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[C:21]([C:28]([OH:30])([CH3:1])[CH3:29])=[CH:20][N:19]=1
Reactant: Cc1ccccc1
Reactant: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C=O
Agent: [Li]C
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(C)(O)c1cnc(Cl)nc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To a 1.0 M solution of TiCl4 in toluene (6.67 mL, 6.67 mmol) was added a 1.6 M solution of MeLi in Et2O (4.18 mL, 6.69 mmol) dropwise a −78° C. (dry ice/acetone bath). The resulting dark solution stirred at −78° C. for 30 minutes. A solution of 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (500 mg, 2.23 mmol) in Et2O (3 mL) was added dropwise at −78° C. The reaction was slowly allowed to warm to rt in the dewar over a 15 h period. TLC analysis showed complete conversion to the more polar tertiary alcohol product. The mixture was then cooled to 0° C. and quenched with sat. aq. NH4Cl (10 mL) followed by EtOAc (10 mL) for the workup. The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (2×10 mL). The EtOAc layers were combined, dried using Na2SO4 and evaporated to give the crude product. Purification using ISCO FCC eluting with 20% EtOAc in Hexanes gave 459 mg of 2-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol (86% yield) as a colorless oil. LC-MS MS (ESI) m/z 241.12 [M+H]+. 1H NMR (CDCl3, 400 MHz): δ 9.05 (s, 1H), 1.99 (s, 1H), 1.67 (s, 6H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[F:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])[NH:24][NH2:25])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:26])[NH:24][N:25]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])=[CH:20][CH:21]=1
Reactant: NNC(=O)Nc1ccc(F)cc1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccc(F)cc1

Procedure:
ninhydrin, 4-(4-fluorophenyl)-semicarbazide hydrochloride
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]#[C:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1.[CH:22]([C:24]1[C:25]([OH:38])=[CH:26][C:27]2[C:28]([CH3:37])([CH3:36])[CH2:29][CH2:30][C:31]([CH3:35])([CH3:34])[C:32]=2[CH:33]=1)=[O:23].O>CN(C)C=O>[CH:22]([C:24]1[C:25]([O:38][CH2:8][C:9]#[C:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)=[CH:26][C:27]2[C:28]([CH3:37])([CH3:36])[CH2:29][CH2:30][C:31]([CH3:34])([CH3:35])[C:32]=2[CH:33]=1)=[O:23]
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(O)cc21
Reactant: CCOC(=O)c1ccc(C#CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(C#CCOc2cc3c(cc2C=O)C(C)(C)CCC3(C)C)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
0.71 g of potassium carbonate and 1.0 g of ethyl 4-(3-bromo-1-propynyl)benzoate were added to 20 ml of a solution of 0.80 g of 3-formyl-5,6,7,8-tetrahydro-2-hydroxy-5,5,8,8-tetramethylnaphthalene in anhydrous N,N-dimethyl formamide at room temperature. The obtained mixture was stirred at 50° C. for 30 minutes, followed by the addition thereto of 20 ml of water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography (developer: 20% diethyl ether/n-hexane) to give 0.87 g of the title compound as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[CH3:22][C:23]1[CH:27]=[CH:26][S:25][C:24]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:24]3[S:25][CH:26]=[CH:27][C:23]=3[CH3:22])[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cc1ccsc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3sccc3C)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed stirred solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 3-methylthiophene-2-boronic acid pinacol ester (129 mg, 0.575 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(3-methylthiophen-2-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.24 (s, 1H), 7.1-7.2 (m, 2H), 7.0 (dd, 1H), 6.6 (s, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 3.64 (m, 1H), 3.2 (m, 1H), 2.8-3.17 (m, 7H), 2.6 (t, 2H), 2.4 (s, 3H), 2.2 (t, 2H), 1.8 (m, 3H).
Reaction SMILES: C1C2C(CO[C:16]([N:18](C)[N:19]([CH2:21][C:22]3[N:23]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])=O)C3C(=CC=CC=3)C=2C=CC=1.CN(C)C(=O)C>N1CCCCC1>[CH3:20][N:19]([CH2:21][C:22]1[N:23]([CH2:31][CH2:32][C:33]([O-:35])=[O:34])[C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:18][CH3:16].[NH2+:23]1[CH2:24][CH2:29][CH2:33][CH2:32][CH2:31]1
Reactant: CN(Cc1cc2ccccc2n1CCC(=O)O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CC(=O)N(C)C
Solvent: C1CCNCC1
Product: C1CC[NH2+]CC1
Product: CNN(C)Cc1cc2ccccc2n1CCC(=O)[O-]
Reaction time: 0.33 h

Procedure:
Compound 4 was synthesized from Compound 3 as follows. Indole 3 (64.2 mg, 133 μmol) was dissolved in a solution of piperidine in in N,N-dimethylacetamide (20% v/v, 1.31 mL, 2.65 mmol, 20.0 equiv). After 20 min, the solution was purified by C18 silica gel chromatography (0-100% acetonitrile in water). The product was isolated as a colorless oil (28.4 mg, 82.0 μmol, 62%). 1H NMR (400 MHz, 7:5 D2O:CD3CN) δ 7.84 (d, J=7.9 Hz, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.49 (m, 1H), 7.36 (m, 1H), 6.73 (s, 1H), 4.73-4.69 (m, 2H), 4.25 (s, 2H), 3.36-3.29 (m, 4H), 2.86-2.80 (m, 2H), 2.78 (s, 3H), 2.67 (s, 3H), 1.99-1.95 (m, 4H), 1.88-1.83 (m, 2H). 13C NMR (151 MHz, 7:5 D2O:CD3CN) δ 179.80, 137.61, 135.78, 128.40, 122.59, 121.29, 120.50, 110.94, 103.70, 53.86, 45.32, 42.79, 41.43, 38.64, 33.95, 23.07, 22.41, 1.32. HRMS (ESI) calcd for C14H20N3O2 [M-piperidine+H]+: 262.1556. found: 262.1547.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[CH2:4]=[C:5]([CH3:7])[CH3:6].[CH2:8](O)[CH:9]([CH3:11])[CH3:10]>CC(OC)(C)C>[CH3:4][C:5]([O:3][CH3:1])([CH3:7])[CH3:6].[CH3:2][CH2:1][O:3][C:9]([CH3:11])([CH3:10])[CH3:8]
Reactant: C=C(C)C
Reactant: CC(C)CO
Reactant: CCO
Solvent: COC(C)(C)C
Product: CCOC(C)(C)C

Procedure:
The process according to claim 9 wherein the stream (I) is added to the isobutene produced by the dehydration of isobutanol to produce MTBE or mixtures of MTBE/ETBE.
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:17]([O:18]C(=O)C)[C@H:16]([O:22]C(=O)C)[C@@H:15]([CH2:26][O:27]C(=O)C)[O:14][C@@H:9]1[O:10][CH2:11][CH2:12][Br:13])(=O)C>CO>[Br-:13].[O:10]([CH2:11][CH2:12][Br:13])[C@H:9]1[O:14][C@H:15]([CH2:26][OH:27])[C@@H:16]([OH:22])[C@H:17]([OH:18])[C@H:8]1[OH:7]
Reactant: CC(=O)OC[C@H]1O[C@H](OCCBr)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@H](OCCBr)[C@H](O)[C@@H](O)[C@@H]1O
Product: [Br-]
Reaction time: 6 h
Yield: 147 %

Procedure:
A solution of NaOMe (0.1 M, 0.3 mL) was added to a suspension of 4g (See FIG. 6) (300 mg, 0.66 mmol) in MeOH (3 mL) under N2 and stirred vigorously. After 6 hours, the resulting solution was passed through a Dowex 50W(H+) plug (2×1 cm, eluant MeOH) and the solvent removed to give 2-bromoethyl α-D-glucopyranoside bromide (4b) (See FIG. 6) (178 mg, 94%) (The synthesis of 4b as an intermediate has been described previously. However, this method gave only a poor yield of product. Nagai et al., Carbohydr. Res., 190:165-180 (1989), which is hereby incorporated by reference) as a white solid. NaSSO2CH3 (100 mg, 0.75 mmol) was added to a solution of 4b (See FIG. 6) (178 mg, 0.62 mmol) in DMF (7 mL) under N2 and warmed to 50° C. After 25 hours, the solution was cooled and the solvent removed. The residue was purified by flash chromatography (MeOH:EtOAc, 1:9) to give 1b (See FIG. 6) (144 mg, 73%) as a hygroscopic foam; [α]27D=+109.9 (c 1.11, H2O); IR (film) 3423 cm−1 (OH), 1309, 1128 cm−1 (S—SO2); 1H NMR (500 MHz, D2O, COSY) δ 3.16 (t, J9.5 Hz, 1H, H-4), 3.28 (t, J5.9 Hz, 2H, —CH2S—), 3.30 (s, 3H, CH3SO2—), 3.31 (dd, J1,2 3.8 Hz, J2,3 9.9 Hz, 1H, H-2), 3.44 (t, J9.5 Hz, 1H, H-3), 3.47-3.53 (m, 2H, H-6, H-6′), 3.58-3.61 (m, 1H, H-5), 3.62 (dt, Jt 5.4 Hz, Jd 10.8 Hz, 1H, —OCHH′—), 3.79 (dt, Jt 6.3 Hz, Jd 10.8 Hz, 1H, —OCHH′), 4.72 (d, J1,2 3.8 Hz, 1H, H-1); 13C NMR (100 MHz, D2O) δ 36.7 (—CH2S—), 50.7 (CH3SO2—), 61.5 (—OCH2—), 67.2, 70.5, 72.3, 73.2, 74.0 (C-2, C-3, C-4, C-5, C-6), 99.4 (C-1); HRMS m/z (FAB+): Found 319.0517 (M+H+); C9H19O8S2 requires 319.0521.
Reaction SMILES: [C:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:16][CH:17]([C:25]([F:28])([F:27])[F:26])[C:18]([F:24])([F:23])[S:19]([O-:22])(=[O:21])=[O:20].[C:29]1([S+:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:24][C:18]([F:23])([S:19]([O-:22])(=[O:21])=[O:20])[CH:17]([O:16][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:15][CH:14]=1)[C:25]([F:28])([F:26])[F:27].[C:42]1([S+:35]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Reactant: C=C(C)C(=O)Oc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc(C(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2.4 g (11 mmol) of the resulting 4-methacryloyloxybenzoic chloride were added 4.9 g (10 mmol) of triphenylsulfonium 2-hydroxy-1,1,3,3,3-pentafluoropropane-1-sulfonate in Synthesis Example 1-11 and 20 g of methylene chloride, which was ice cooled. To the solution, a solution of 1.1 g (11 mmol) of triethylamine and 0.2 g (2 mmol) of N,N-dimethylaminopyridiene in 5 g of methylene chloride was added such that the temperature might not exceed 5° C., followed by stirring at room temperature for 3 hours. Thereafter, 11 g of 5% dilute hydrochloric acid was added. The organic layer was separated and washed with water whereupon methylene chloride was distilled off under vacuum. The residue was combined with 30 g of methyl isobutyl ketone and washed with dilute aqueous ammonia and then with water, whereupon the methyl isobutyl ketone was distilled off under vacuum. The residue was washed with diisopropyl ether and purified by silica gel chromatography. The target compound, triphenylsulfonium 1,1,3,3,3-pentafluoro-2-(4-methacryloyloxy-benzoyloxy)-propane-1-sulfonate was obtained as colorless oil (6.0 g, yield 88%). The compound has the following structure.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8](=[O:40])[NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[N:26]=3)[N:21]=[CH:20][C:19]=2Cl)[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].C(OCC)(=O)C>O.O1CCCC1>[C:3]([O:7][C:8](=[O:40])[NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH2:31][N:32]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:19]3[CH:20]=[N:21][C:22]4[C:27]([C:18]=3[CH:17]=2)=[N:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1ccc2ncc(Cl)c(C=C(CNCc3ccccc3)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2ncc3c(c2n1)C=C([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CN3Cc1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of sodium hydroxide (500 mg, 12.5 mmol, 33.6 eq) in water (6 mL) is added at room temperature to a stirred solution of {trans-4-[1-(benzylamino-methyl)-2-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-vinyl]-cyclohexyl}-carbamic acid tert-butyl ester (200 mg, 0.37 mmol, 1.0 eq) in tetrahydrofuran (6 mL). After 16 hours stirring at 60° C., tetrahydrofuran is removed and the residue is extracted with ethyl acetate (3×10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give the crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1 to 3:1, v/v) to afford [trans-4-(1-benzyl-6-methoxy-1,2-dihydro-1,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester as a light yellow solid (110 mg, 59% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[NH:5][CH:6]([CH3:11])[CH2:7][C:8]([OH:10])=O.[C:15](Cl)([Cl:17])=[O:16].C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12]([C:8](=[O:10])[CH2:7][CH:6]([CH3:11])[N:5]2[C:15]([Cl:17])=[O:16])=[CH:13][CH:14]=1
Reactant: O=C(Cl)Cl
Reactant: CC(CC(=O)O)Nc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1CC(=O)c2ccc(Cl)cc2N1C(=O)Cl

Procedure:
7-Chloro-1-chloroformyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinone is prepared in a manner similar to that described in Example 5 but starting from 3-(3-chloroanilino)butanoic acid (5.42 g; 25.4 mmol), phosgene (6.7 g; 67.7 mmol), methylene chloride (25 cc), dimethylformamide (0.23 cc) and aluminum chloride (8.15 g; 61.1 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH:5]([CH3:36])[CH:6]([C:17]1[C:25]2[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=2)[N:19](C(OC(C)(C)C)=O)[CH:18]=1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH3:2].FC(F)(F)C(O)=O.O>ClCCl>[CH3:36][CH:5]([CH:6]([C:17]1[C:25]2[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:14])[F:16])=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:37]
Reactant: CCOC(=O)C(C)C(c1ccc(C(F)(F)F)cc1)c1cn(C(=O)OC(C)(C)C)c2c(CSC)cccc12
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)C(c1ccc(C(F)(F)F)cc1)c1c[nH]c2c(CSC)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.52 g (4.71 mmol) of the compound from Example 27A were dissolved in 70 ml of dichloromethane, and 14.5 ml (188.56 mmol) of trifluoroacetic acid were added. After stirring at RT for 3 h, the reaction solution was mixed with water, the phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and dried over sodium sulfate, the solid was filtered off and the solvents were removed in vacuo. Purification of the crude product by flash chromatography on silica gel (mobile phase: dichloromethane/methanol 95/5) and preparative HPLC (mobile phase: acetonitrile-water gradient) resulted in 1.01 g (48% of theory) of the title compound as mixture of diasteromers.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:3]=1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([CH:28]=O)[CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O.C(O)(=O)C.ClCCl>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[CH:5]=[C:4]([N:16]2[CH2:17][CH2:18][N:19]([CH2:28][C:25]3[CH:24]=[C:23]([CH3:22])[O:27][N:26]=3)[CH2:20][CH2:21]2)[N:3]=1
Reactant: Cc1cc(C=O)no1
Reactant: Nc1nc(N2CCNCC2)cc2nc(-c3ccco3)nn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(CN2CCN(c3cc4nc(-c5ccco5)nn4c(N)n3)CC2)no1
Temperature: 0 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
Into 15 mL of dichloromethane, 1.50 g (5.26 mmol) of Compound F and 934 mg (8.42 mmol) of 5-methylisoxazole-3-carboxaldehyde were dissolved, and the solution was cooled to 0° C. in an ice bath. Then, 1.5 mL of acetic acid and 1.78 g (8.42 mmol; 1.6 eq.) of sodium triacetoxyborohydride were added thereto, followed by stirring at room temperature overnight. After completion of the reaction, water was added to the reaction mixture, and a 1.0 mol/L aqueous sodium hydroxide solution was further added thereto to adjust the solution to be basic. Then, the mixture was extracted by adding chloroform, and the organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by silica gel column chromatography (2% methanol-chloroform) and then recrystallized from ethanol to obtain 222 mg of Compound 21 as white powder (yield: 11%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([CH3:10])[CH:3]=1.[OH:11]S(O)(=O)=O.[OH2:16]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([OH:11])=[O:16])=[C:4]([CH3:10])[CH:3]=1
Reactant: O
Reactant: Cc1cc(F)ccc1C#N
Reactant: O=S(=O)(O)O
Product: Cc1cc(F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-fluoro-2-methyl-benzonitrile (5.0 g, 37 mmol), H2SO4 (20 mL) and H2O (15 mL) was stirred at 80° C. for 17 h. The reaction mixture was cooled to ambient temperature and intermediate carboxamide collected as a precipitate. The material was used without purification. The intermediate carboxamide (5.7 g) was treated with 85% phosphoric acid (20 mL) and stirred at 150° C. for 18 h. After this time, the reaction mixture was cooled to ambient temperature and treated with water (30 mL). The resulting solution was extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated to afford 4-fluoro-2-methyl-benzoic acid. The material was without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:33][C:12]3[C:13](=[O:32])[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]5)[N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH2:34]=O>CO.C(Cl)Cl.CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:33][C:12]3[C:13](=[O:32])[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][N:27]5[CH3:34])[N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc3cnn(Cc4cccc(OC[C@@H]5CCCCN5)n4)c(=O)c3s2)cc1
Reactant: C=O
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3cnn(Cc4cccc(OC[C@@H]5CCCCN5C)n4)c(=O)c3s2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-(4-methoxyphenyl)-6-({6-[(2S)-piperidin-2-ylmethoxy]pyridin-2-yl}methyl)thieno[2,3-d]pyridazin-7(6H)-one (290 mg, 0.627 mmol) in MeOH/DCM 1:1(15 ml), were added (polystyrylmethyl)trimethylammonium cyanoborohydride (460 mg, 1.881 mmol, 4.1 mmol/g) and formaldehyde (100 μl, 1.25 mmol) followed by AcOH (one drop). After stirring at rt. for 3 h the resin was filtered off and washed with MeOH. The filtrate was collected and evaporated in vacuo. Purification by silica gel flash chromatography using a 25+M Biotage column with EtOAc/MeOH/TEA 100:10:1 gave the title compound as a light yellow solid. Yield: 201 mg (67%). 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.61 (m, 2H), 7.47 (t, 1H, J=7.8 Hz), 7.34 (s, 1H), 6.96 (m, 2H), 6.71 (d, 1H, J=7.3 Hz), 6.63 (d, 1H, J=8.3 Hz), 5.47 (s, 2H), 4.26 (m, 2H), 3.84 (s, 3H), 2.81 (dt, 1H, J=11.5 Hz, J=3.1 Hz), 2.27 (s, 3H), 2.11 (m, 1H), 2.02 (m, 1H), 1.66 (m, 2H), 1.54 (m, 2H), 1.42 (m, 1H), 1.20 (m, 1H). 13C NMR (400 MHz, CDCl3) δ 163.7, 161.1, 157.4, 153.94, 153.88, 140.5, 139.2, 135.4, 133.3, 128.3, 125.5, 117.2, 114.9, 114.2, 110.1, 67.8, 63.1, 57.5, 55.8, 55.6, 43.6, 29.5, 26.0, 24.3. MS (ESI+) 477.25 (M+1H+)
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[N:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Temperature: 150 °C
Yield: 81.9 %

Procedure:
29.2 g (157 mmol) of 1,1-dimethylethyl 1-piperazinecarboxylate, 37 g (157 mmol) of 2,5-dibromopyridine and 21.7 g (157 mmol) of potassium carbonate suspended in 27 ml of dimethyl sulfoxide (DMSO) are introduced into an autoclave. The mixture is then heated at 150° C. for 21 hours. The reaction mixture is allowed to cool to room temperature, it is taken up in ethyl acetate and water and the insoluble material is then separated out by filtration. The aqueous phase is separated out and extracted twice with ethyl acetate, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel, eluting with a 99/1 mixture of dichloromethane and methanol. 44 g of product are thus obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[CH:9][N:4]2[CH:3]=1.C([Li])CCC.[C:22](=[O:24])=[O:23]>C1COCC1.CCCCCC>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[N:7]=[C:5]3[N:4]([CH:9]=2)[CH:3]=[C:2]([C:22]([OH:24])=[O:23])[S:6]3)=[CH:11][CH:12]=1
Reactant: Fc1ccc(-c2cn3cc(Br)sc3n2)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1cn2cc(-c3ccc(F)cc3)nc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10 %

Procedure:
To a solution of 2-bromo-6-(4-fluoro-phenyl)-imidazo[2,1-b]thiazole (example 22, 100 mg, 0.336 mmol) in 5 ml THF were added 200 μl butyllithium (2.5 M) in hexane at −60° C. The mixture was stirred for 10 min, solid carbon dioxide was added and the mixture was allowed to warm at RT. The solution was quenched with methanol and water, acidified and extracted with ethyl acetate. The organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 9 mg (10%) of the desired product. MS: M+H+=263.03.