Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[C:21](Cl)[N:20]=[C:19]([C:24]#[N:25])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]1[C:29]2([CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31][CH2:30]2)[CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[C:21]([NH:36][CH2:35][CH:32]3[CH2:31][CH2:30][C:29]4([CH2:28][CH2:27][CH2:26]4)[CH2:34][CH2:33]3)[N:20]=[C:19]([C:24]#[N:25])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCC1CCC2(CCC2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2cc(Cl)nc(C#N)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2cc(NCC3CCC4(CCC4)CC3)nc(C#N)n2)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 4-[2-(6-chloro-2-cyanopyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester (0.82 mmol) and C-spiro[3.5]non-7-ylmethylamine (0.86 mmol) in CH3CN (10 mL) is added K2CO3 (2.2 mmol) at room temperature. After stirring at 80° C. for 12 h, the reaction mixture is cooled to room temperature and diluted with AcOEt. The organic layer is washed twice with H2O and dried over MgSO4 and evaporated in vacuo to give a crude 4-(2-{2-cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH2:20]NC)[CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.[CH3:30][O-:31].[Na+].ClCCl.CO>O1CCCC1>[CH3:30][O:31][CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][N:17]=1)[C:13]([NH:12][C:10]1[S:11][C:7]2[C:6]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:23]
Reactant: CNCc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Temperature: 50 °C
Yield: 25 %

Procedure:
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methylaminomethyl-isonicotinamide (200 mg, 0.48 mmol, dissolved in tetrahydrofurane (5.0 ml), is treated with sodium methoxide (81 mg, 1.4 mmol) at 0° C. and the mixture heated to 50° C. for 15 h. The mixture is quenched with saturated sodium carbonate (4.0 ml), extracted four times with each 15 ml dichloromethane and the combined organic phases dryed and evaporated. Flash chromatography (first SiO2, eluent: dichloromethane/methanol 0 to 5% and second dichloromethane/ethyl acetae 30% to 60%) afforded the title compound as light yellow crystals (49 mg, 25% yield). MS: m/e=415 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][C:5]=2[C:6]=1[C:7](OCC)=[O:8].C(O)(=O)C.[CH:25](N)=[NH:26]>C(N)=O.CCOC(C)=O>[OH:8][C:7]1[C:6]2[C:5]3[CH2:12][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:15][C:4]=3[S:3][C:2]=2[N:1]=[CH:25][N:26]=1
Reactant: CCOC(=O)c1c(N)sc2c1CC(C(=O)OCC)CC2
Reactant: N=CN
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: NC=O
Product: CCOC(=O)C1CCc2sc3ncnc(O)c3c2C1
Temperature: 180 °C
Reaction time: 4 h
Yield: 54.8 %

Procedure:
A solution of 3,5-diethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3,5-dicarboxylate (8 g, 26.90 mmol, 1.00 equiv) in formamide (150 mL) was added formamidine acetate (10 g, 96.05 mmol, 3.57 equiv) at room temperature under nitrogen. The resulting solution was stirred for 4 h at 180° C. After cooling, the resulting solution was diluted with 200 mL of EtOAc, washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) give the desired ethyl 4-hydroxy-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate (4.1 g, 55%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:12][C:13]1[C:21]2[N:20]=[C:19]([S:22][C:23]3[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=3)[NH:18][C:17]=2[CH:16]=[C:15]([F:30])[C:14]=1[F:31].[C:32]1(=O)[CH2:37][CH2:36][CH2:35][C:34](=[O:38])[CH2:33]1>C(O)CCC>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:28]([C:26]3[O:27][C:23]([S:22][C:19]4[NH:18][C:17]5[CH:16]=[C:15]([F:30])[C:14]([F:31])=[C:13]([F:12])[C:21]=5[N:20]=4)=[CH:24][CH:25]=3)[C:33]3[C:34](=[O:38])[CH2:35][CH2:36][CH2:37][C:32]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: O=C1CCCC(=O)C1
Reactant: O=Cc1ccc(Sc2nc3c(F)c(F)c(F)cc3[nH]2)o1
Reactant: CCOC(=O)c1[nH]ccc1N
Solvent: CCCCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3c(F)c(F)c(F)cc3[nH]2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.2 %

Procedure:
A suspension of 190 mg (1.23 mmol) of 3-amino-2-ethoxycarbonylpyrrole and 367 mg (1.23 mmol) of 5-(4,5,6-trifluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (obtained from step 2) in 6.5 mL of n-butanol under argon is stirred at room temperature for 15 minutes. 1,3-Cyclohexanedione (138 mg, 1.23 mmol) is then added and the reaction mixture is heated at reflux temperature for 2 h. The mixture is then cooled to room temperature and concentrated under reduced pressure. The residue is taken up in 5 mL of ethanol, cooled to 0° C. and triturated. The solid is filtered, washed with 1 mL of ethanol and 3 times with 5 mL of diisopropylether and dried under reduced pressure. 144 mg of 8-oxo-9-[5-(4,5,6-trifluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester are obtained as a yellow crystalline powder. mp: 186° C. LCMS-DAD-ELSD: 527(−): [M−H]−; 529(+): [M+H]+.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.ClC(O[C:11](=[O:17])OC(Cl)(Cl)Cl)(Cl)Cl.[F:18][C:19]1[CH:20]=[C:21]2[N:27]([C:28]3[N:33]=[C:32]([NH2:34])[C:31]([NH2:35])=[C:30]([NH2:36])[N:29]=3)[N:26]=[C:25]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[F:44])[C:22]2=[N:23][CH:24]=1.C(=O)(O)[O-].[Na+]>ClCCl.N1C=CC=CC=1>[NH2:36][C:30]1[C:31]([NH:35][C:11](=[O:17])[O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[C:32]([NH2:34])[N:33]=[C:28]([N:27]2[C:21]3[C:22](=[N:23][CH:24]=[C:19]([F:18])[CH:20]=3)[C:25]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[F:44])=[N:26]2)[N:29]=1
Reactant: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc(N)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc(N)c1NC(=O)OC1CCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 64 ml (0.81 mmol) of cyclobutyl alcohol were initially charged in dichloromethane (4.1 ml), 161 mg (0.54 mmol) of bis(trichloromethyl)carbonate were then added and the mixture was cooled to 0° C. 53 μl (0.65 mmol) of pyridine were then added dropwise, and the reaction mixture was stirred at 0° C. for another 30 min. 200 mg (0.54 mmol) of the compound from example 6A were then added, and the mixture was diluted with 1.4 ml of pyridine. The reaction mixture was stirred at RT overnight, saturated aqueous sodium bicarbonate solution was then added and the mixture was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by means of preparative RP-HPLC (acetonitrile:water (+0.1% formic acid)−gradient) and the product fractions were concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: Cc1cc(Cl)nc(N2CCCC2)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cc(C)nc(N3CCCC3)n2)ccc1-n1cnc(C)c1
Yield: 58 %

Procedure:
The title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.30 mmol) and 4-chloro-6-methyl-2-pyrrolidin-1-yl-pyrimidine (65 mg, 0.33 mmol, example 95a) in analogous manner as described in example 90. The crude product was purified by stirring with diethyl ether. It was obtained in 58% yield as a light brown solid. MS ISP (m/e): 365.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.30 (s, 1H), 8.06 (s, 1H), 7.65 (s, 1H), 7.21 (d, 1H), 7.15 (d, 1H), 7.02 (s, 1H), 5.91 (s, 1H), 3.81 (s, 3H), 3.50 (br m, 4H), 2.15 (s, 3H), 2.14 (s, 3H), 1.90 (br m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH2:8][CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].[NH:35]([C:39]1[S:40][CH:41]=[C:42]([CH2:44][S:45][CH2:46][CH2:47][NH2:48])[N:43]=1)[C:36]([NH2:38])=[NH:37]>C(OCC)(=O)C.CO>[NH:35]([C:39]1[S:40][CH:41]=[C:42]([CH2:44][S:45][CH2:46][CH2:47][NH:48][C:23]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH2:8][CH2:9][CH:10]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH3:1])=[O:24])[N:43]=1)[C:36]([NH2:38])=[NH:37]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: CN(CCCCN)CCC(c1ccccc1)c1ccccn1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCCCNC(=O)NCCSCc1csc(NC(=N)N)n1)CCC(c1ccccc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.89 g (3 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,4-butanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.75 g (3.2 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography (eluant: chloroform/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%])=555 ([M+H]+ 1), 196 (100); IR (KBr): 1610 cm-1 (C=O). For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/ethanol; m.p.: from 80° C. with decomposition.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[CH:35]=[CH:34][C:19]([CH2:20][C:21]2[O:25][N:24]=[C:23]([C:26]3[C:27]([NH2:33])=[N:28][CH:29]=[C:30]([Cl:32])[CH:31]=3)[CH:22]=2)=[CH:18][CH:17]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>O>[NH2:33][C:27]1[C:26]([C:23]2[CH:22]=[C:21]([CH2:20][C:19]3[CH:34]=[CH:35][C:16]([OH:15])=[CH:17][CH:18]=3)[O:25][N:24]=2)=[CH:31][C:30]([Cl:32])=[CH:29][N:28]=1
Reactant: Nc1ncc(Cl)cc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)on1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CSc1ccccc1
Product: Nc1ncc(Cl)cc1-c1cc(Cc2ccc(O)cc2)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
To a trifluoroacetic acid (6 mL) solution of 3-(5-(4-benzyloxy-benzyl)-isoxazol-3-yl)-5-chloro-pyridin-2-ylamine (304 mg, 0.776 mmol) described in Manufacturing Example 29-2-3 was added thioanisole (364 mL, 3.10 mmol) at 0° C., which was stirred for 3 hours at room temperature. To this reaction mixture were added sodium hydrogencarbonate and water at 0° C., which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) to obtain the title compound (146 mg, 62%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:11])=[CH:2]1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([O:12][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[CH:2]=1)=[O:11])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(CCCBr)OCc1ccccc1
Reactant: CCCCCCCCCOC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCOC(=O)c1cn(CCCC(=O)OCc2ccccc2)c2ccccc12
Yield: 92.4 %

Procedure:
A mixture of nonyl indole-3-carboxylate (251 mg) obtained in Pre. Ex. 30, benzyl 4-bromobutyrate (449 mg) and potassium carbonate (362 mg) in N,N-dimethylformamide was stirred at 50° C. for 6 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated. Silica gel column chromatography of the concentrate afforded benzyl 4-(3-nonyloxycarbonyl-1-indolyl)butyrate (374 mg) as an oil.
Reaction SMILES: Cl[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[Cl:8].[NH2:11][C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=2)[N:22]=[CH:21][N:20]=1>>[Cl:8][C:7]1[CH:6]=[N:5][N:4]([CH3:9])[C:3](=[O:10])[C:2]=1[O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][N:20]=[C:19]2[NH:11][C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4c(Cl)cnn(C)c4=O)cc23)n1

Procedure:
The compound of Example 127 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 4,5-dichloro-2-methyl-3(2H)pyridazinone, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:15][CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[C:6]=2[CH:7]=1.O1CCCC1.C([Li])CCC.[C:26](=[O:28])=[O:27]>CCCCCC>[O:9]1[CH2:10][CH2:11][O:12][C:8]21[C:6]1[CH:7]=[C:2]([C:26]([OH:28])=[O:27])[CH:3]=[CH:4][C:5]=1[S:15][CH2:14][CH2:13]2
Reactant: O=C=O
Reactant: Brc1ccc2c(c1)C1(CCS2)OCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1ccc2c(c1)C1(CCS2)OCCO1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
13.58 g (0.047 mol) of the title compound of Step C was added to 150 mL of tetrahydrofuran. The solution was cooled to about -65° C. and 23 mL (0.057 mol) of 2.5 M n-butyllithium in hexane (purchased from Aldrich Chemical Company) was added dropwise while keeping the temperature below -55° C. After stirring under nitrogen for 1 h, excess solid CO2 was added in one portion, and the mixture was stirred overnight while warming to room temperature. 100 mL of hexane was added to the mixture, and it was then filtered. To the solid residue was added 500 mL of water and 400 mL of methylene chloride. The solution was cooled to about 0° C., acidified to pH 1 with concentrated hydrochloric acid, and extracted with methylene chloride (3×400 mL). The resulting solution was dried (MgSO4), filtered, and evaporated to dryness to yield 8.58 g of the title compound of Step D as a solid melting at 186.7° C. (dec). 1H NMR (Me2SO-d6): δ2.2 (m,2H), 3.2 (m,2H), 4.1 (m,4H), 7.2-8.0 (3H), 12.8 (br s,1H).
Reaction SMILES: CO[CH:3](O)[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([F:15])[CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:16].CC(N([C@H]1CCNC[C@H]1O)C(=O)[O-])(C)C.[C:33]([O:37][C:38](=[O:47])[NH:39][C@H:40]1[CH2:45][CH2:44][NH:43][CH2:42][C@H:41]1[OH:46])([CH3:36])([CH3:35])[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[F:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][C:6](=[O:16])[N:5]2[CH2:4][CH2:3][N:43]2[CH2:44][CH2:45][C@H:40]([NH:39][C:38](=[O:47])[O:37][C:33]([CH3:34])([CH3:35])[CH3:36])[C@H:41]([OH:46])[CH2:42]2)=[N:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC[C@H]1O
Reactant: COC(O)Cn1c(=O)ccc2ncc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)N(C(=O)[O-])[C@H]1CCNC[C@H]1O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(7-Fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde methyl hemiacetal (200 mg, 0.8396 mmol) and 1,1-dimethylethyl[(3R,4S)-3-hydroxy-4-piperidinyl]carbamate (for a synthesis see WO2004058144, Example 5(c), cis-(3-hydroxy-piperidin-4-yl)-carbamic acid tert-butyl ester Enantiomer 1) (182 mg, 1 eq.) were stirred in chloroform (10 ml) plus MeOH (0.5 ml) under argon for 2 hours. Sodium triacetoxyborohydride (534 mg, 3 eq.) was added in one portion and the mixture was stirred at rt overnight, then quenched by addition of saturated aqueous sodium hydrogen cabonate (20 ml) and extracted with 20% v:v MeOH in DCM (3×200 ml). The organic extractes were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica, eluted with 0-20% (2M ammonia in MeOH) in DCM. Appropriate fractions were combined and evaporated under reduced pressure to give title compound (247 mg) as an off-white foam.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1.[Si:27]([O:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH:44]=O)=[CH:39][CH:38]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1>[Si:27]([O:34][CH2:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:43][CH2:44][N:24]2[CH2:25][CH2:26][C:20]3([O:19][CH2:18][CH2:17][N:16]([C:14]([C:12]4[N:13]=[C:9]([CH3:8])[S:10][CH:11]=4)=[O:15])[CH2:21]3)[CH2:22][CH2:23]2)=[CH:41][CH:42]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(CC=O)cc1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCO[Si](C)(C)C(C)(C)C)cc4)CC3)C2)cs1
Reaction time: 0.08 h

Procedure:
(2-Methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 4, step h) (0.26 g) was added to a solution of 2-(4-(2-(tert-butyldimethylsilyloxy)ethyl)phenyl)acetaldehyde (example 5, step c) (0.2 g) and acetic acid (0.04 mL) in NMP (5 mL). The resulting mixture was stirred for 5 min then sodium triacetoxyborohydride (0.23 g) was added. The mixture was stirred for 1 h, poured into pH 7.2 buffer (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic solutions were washed with pH 7.2 buffer (50 mL) and brine (50 mL), then dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 80:15:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine to give the subtitled compound as a yellow oil. Yield 0.30 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:17]3[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]3[O:19][C:20](=[O:22])[CH3:21])=[N:12][NH:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1.[C:40](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:17]3[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]3[O:19][C:20](=[O:22])[CH3:21])=[N:12][N:13]([CH3:40])[C:14]=2[CH3:15])=[CH:7][CH:8]=1
Reactant: COc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)nn(C)c2C)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
A suspension of 4-[(4-methoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (18 mg), potassium carbonate (14 mg) and iodomethane (4.7 mg) in acetonitrile (2 mL) was stirred at 75° C. overnight. The reaction mixture was filtered through celite®, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: benzene/acetone=2/1) to give 4-[(4-methoxyphenyl)methyl]-1,5-dimethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)pyrazole (4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: OB(O)c1ccccc1F
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccccc2F)c1
Yield: 73.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 2-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.051 g (73%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-3-carboxamide as a white solid.
Reaction SMILES: FC1C=CC([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][C:21]=3[O:35][CH3:36])[N:10]=2)=C(C(=O)NC)C=1.ClC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2OC)N=1.N[C:71]1[C:80]([F:81])=[CH:79][CH:78]=[CH:77][C:72]=1[C:73]([NH:75][CH3:76])=[O:74]>>[F:81][C:80]1[CH:79]=[CH:78][CH:77]=[C:72]([C:73](=[O:74])[NH:75][CH3:76])[C:71]=1[NH:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][C:21]=2[O:35][CH3:36])[N:10]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(F)cc3C(=O)NC)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1cccc(F)c1N
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3c(F)cccc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)-phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate) using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 2-amino-3-fluoro-N-methylbenzamide. 1H NMR (CDCl3, 400 MHz): δ=1.26 (t, J=7.07 Hz, 6H), 2.92 (d, J=4.80 Hz, 3H), 3.03-3.12 (m, 2H), 3.86 (s, 3H), 3.95-4.07 (m, 4H), 6.21 (q, J=4.97 Hz, 1H), 6.57 (d, J=9.09 Hz, 1H), 6.81 (t, J=1.89 Hz, 1H), 7.28-7.36 (m, 3H), 7.73 (br. s., 1H), 7.85 (br. s., 1H), 8.34 (s, 1H), 8.89 (br. s., 1H). MS (ES+): m/z 586.14 [MH+] (TOF, polar).