Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:8]2)=[CH:4][CH:3]=1.Cl.[N:28]1[CH:33]=[CH:32][C:31]([CH2:34]Cl)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C.O1CCCC1.O.CN(C)C=O>[C:12]1([C:10]2[C:9]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:34][C:31]4[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=4)=[CH:26][CH:25]=3)[CH:11]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClCc1ccncc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccncc3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (1.10 g), 4-picolyl chloride hydrochloride (0.60 g), potassium carbonate (0.88 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and an oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). A mixture of the oily substance obtained, 1N aqueous sodium hydroxide solution (6 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After adding water, the residue was neutralized by adding 1N hydrochloric acid. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-(4-pyridylmethoxy)benzyl]-3-pyrrolyl]propionic acid (0.98 g, yield: 75%). This was recrystallized from acetone-hexane. Melting point: 124–125° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[C:24]([CH3:26])[N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[CH3:28][N:29]([CH3:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:27][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[C:24]([CH3:26])[N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([N:29]([CH3:38])[CH3:28])=[CH:31][CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cc1csc(NC(=O)CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)n1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1csc(NC(=O)CN2CCN(c3c(Cl)cnc4[nH]c(-c5ccc(N(C)C)cc5)nc34)CC2)n1
Temperature: 70 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(4-methylthiazol-2-yl)acetamide (0.034 g, 0.08 mmol), ethanol (3 ml), and 4-dimethylaminobenzaldehyde (0.015 g, 0.10 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.35 ml, 0.35 mmol). The reaction mixture was heated at 70° C. for 3.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 40% ethyl acetate in dichloromethane and then 2.5% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.010 g, 25%); 1H-NMR (500 MHz, DMSO-d6) 2.27 (s, 3H, CH3), 2.76 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.71 (br s, 4H, piperazine N(CH2)2), 3.37 (s, 2H, NCH2CO), 6.77 (s, 1H, thiazole 5-H), 6.81 (d, J=8.91 Hz, 2H) and 8.01 (d, J=8.88 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 8.03 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.78 (s, 1H, CONH), 13.09 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].Cl[C:16]1[CH:17]=[C:18]([B:23]2[NH:34][C:33]3[C:35]4[C:29]([CH:30]=[CH:31][CH:32]=3)=[CH:28][CH:27]=[CH:26][C:25]=4[NH:24]2)[CH:19]=[CH:20][C:21]=1[F:22].P([O-])([O-])[O-].[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CN(C=O)C>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[C:18]([B:23]3[NH:24][C:25]4[C:35]5[C:29]([CH:28]=[CH:27][CH:26]=4)=[CH:30][CH:31]=[CH:32][C:33]=5[NH:34]3)[CH:17]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: Fc1ccc(B2Nc3cccc4cccc(c34)N2)cc1Cl
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [K+]
Agent: [O-]P([O-])[O-]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(-c2cc(B3Nc4cccc5cccc(c45)N3)ccc2F)cc1
Reaction time: 12 h
Yield: 42 %

Procedure:
To a room temperature solution of 4-(ethylsulphonyl)benzeneboronic acid (0.90 g, 4.22 mmol) in anhydrous DMF (20 mL) was added 2-(3-chloro-4-fluorophenyl)-2,3-dihydro-1H-1,3-diaza-2-boraphenalene (Preparation 81, 1.00 g, 3.37 mmol) and potassium phosphite (2.87 g, 13.5 mmol) and the reaction mixture was degassed with argon for 30 minutes. To this was added 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (276.7 mg, 0.67 mmol) followed by the tris(dibenzilideneacetone)palladium(0) (154 mg, 0.168 mmol) and the resultant solution was heated to 100° C. with stirring for 12 hours. The reaction mixture was cooled then filtered through a pad of celite. The pad was rinsed well with EtOAc (100 mL) and the filtrate was washed with water (2×50 mL) then saturated brine solution and dried over anhydrous MgSO4 (s), filtered and evaporated in vacuo to give crude product as a yellow oil. The residue was purified by silica gel column chromatography eluting with CH2Cl2:MeOH 98:2 to afford the title compound as a colourless oil in 42% yield, 600 mg.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:21][CH:20]=1)[C:13]([C:35]1[CH:40]=[CH:39][C:38]([O:41]CC3C=CC=CC=3)=[CH:37][CH:36]=1)=[C:12]2[CH3:49])C1C=CC=CC=1>O1CCCC1.C(O)C>[OH:41][C:38]1[CH:39]=[CH:40][C:35]([C:13]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)=[CH:21][CH:20]=3)[C:15]3[C:11]([C:12]=2[CH3:49])=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)=[CH:36][CH:37]=1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc12
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(O)cc2)n(Cc2ccc(OCCCN3CCCCC3)cc2)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-3methyl-1H-indole No. 165 (2.35 g) in tetrahydrofuran (25 mL) and ethanol (25 mL) was added to 2.3 g of 10% palladium on carbon Cyclohexadiene (10 mL) was added and the reaction allowed to stir at room temperature for 18 hours. The catalyst was filtered through celite and the reaction mixture was concentrated and chromatographed on silica gel using dichlomaethane/methanol (4:1) to elute the product (0.8 g) as a white foam: Mp=125-130° C., 1H NMR 9.68 (s, 1H), 8.70 (s, 1H), 7.15 (d, 2H, J=8.6 Hz), 7.05 (d, 1H, J=8.8 Hz), 6.85 (d, 2H, J=8.6 Hz), 6.80 (d, 1H, J=2.4 Hz), 6.74 (d, 4H, J=2.6 Hz), 6.57 (dd, 1H, J=8.6, 2.2 Hz), 5.09 (s, 2H), 3.88 (t, 2H, J=6.4 Hz), 3.60-3.15 (m, 2H), 2.62-2.38 (m, 4H), 2.09 (s, 3H), 1.92-1.78 (m, 2H), 1.55-1.43 (m, 4H), 1.42-1.30 (m, 2H); IR (KBr) 3400 (br), 2900, 1620, 1515 cm−1; MS eI m/z 470.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:38]=[CH:37][C:24]([CH2:25][N:26]4[CH2:29][CH:28]([C:30]([O:32]C(C)(C)C)=[O:31])[CH2:27]4)=[CH:23][CH:22]=3)[N:17]=2)=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:2]([CH3:4])[CH3:3].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[C:6]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[CH:23][C:24]([CH2:25][N:26]4[CH2:27][CH:28]([C:30]([OH:32])=[O:31])[CH2:29]4)=[CH:37][CH:38]=3)[N:17]=2)=[N:7][O:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1c(-c2nc(-c3ccc(CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1c(-c2nc(-c3ccc(CN4CC(C(=O)O)C4)cc3)no2)noc1-c1ccccc1

Procedure:
The tert-butyl 1-(4-(5-(4-isobutyl-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)-azetidine-3-carboxylate intermediate was stirred in trifluoroacetic acid (3.64 mL, 47.2 mmol) for 30 min. and concentrated under reduced pressure to give the desired product as a pale yellow solid. The solid was dispersed in water with some methanol with sonication. The pH was adjusted to ˜4, and the resulting solid was collected by vacuum filtration, washed with water (3×), and dried. The white solid was triturated with methanol with sonication and filtered to give 1-(4-(5-(4-isobutyl-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (0.074 g, 0.161 mmol, 34.2% yield) as a white, crystalline solid. The compound had an HPLC ret. time=2.99 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=459.3. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.60 Hz, 6H), 1.93 (ddd, J=13.61, 6.74, 6.60 Hz, 1H), 2.99 (d, J=7.15 Hz, 2H), 3.24 (br. s., 3H), 3.43 (s, 2H), 3.66 (s, 2H), 7.53 (d, J=7.70 Hz, 2H), 7.58-7.67 (m, 3H), 7.87 (d, J=6.60 Hz, 2H), and 8.06 (d, 2H). The methanol filtrate was concentrated under reduce pressure to give additional 1-(4-(5-(4-isobutyl-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (0.034 g, 0.066 mmol, 13.99% yield) as a pale yellow solid (HPLC purity=89%).
Reaction SMILES: [Li+].[Cl-].C(COC)OC.Br[C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].[C:18]1([CH3:26])[CH:23]=[CH:22][C:21]([Mg]Cl)=[CH:20][CH:19]=1>O1CCCC1>[C:18]1([CH3:26])[CH:23]=[CH:22][C:21]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:20][CH:19]=1
Reactant: Cc1ccc([Mg]Cl)cc1
Reactant: N#Cc1ccccc1Br
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of MnCl2 (0.25 g, 1.98 mmol) and LiCl (0.17 g, 3.955 mmol) in a mixture of 2 ml of anhydrous tetrahydrofuran and 0.38 ml of dimethoxyethane (3.955 mol) is stirred at room temperature until, after approximately 30 minutes, a homogeneous medium is obtained. The PdCl2/dppp complex (0.0023 g, 0.1 mol %) and the o-bromobenzonitrile (0.72 g, 3 955 mmol) are then added and then a solution of p-tolylmagnesium chloride in tetrahydrofuran (1.80N, 2.86 ml, 5.14 mmol) is added over 30 minutes. After stirring for 30 minutes, the reaction mixture is treated as described in Example 4. The o-(p-tolyl)benzonitrile is thus obtained with a yield of isolated product of 95%.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15]2[N:20]=[C:19]([NH2:21])[C:18]([N:22]=NC3C=CC=CC=3)=[C:17]([NH2:30])[N:16]=2)=[N:6]1.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].CC#N.CO.C(Cl)Cl>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15]2[N:20]=[C:19]([NH2:21])[C:18]([NH2:22])=[C:17]([NH2:30])[N:16]=2)=[N:6]1
Reactant: Nc1nc(-c2nc(-c3nccs3)n(Cc3ccccc3F)n2)nc(N)c1N=Nc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1nc(-c2nc(-c3nccs3)n(Cc3ccccc3F)n2)nc(N)c1N
Temperature: 150 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine (Intermediate-7, 0.38 mmol) in DMF (2.5 mL) was added sodium hydroxide solution (2N, 3 equiv) and sodium dithionite (5.5 equiv). The reaction was heated to 150° C. and stirred for 2 h. The reaction mixture was diluted with CH2Cl2 and filtered. The filtrate was conc. and purified using SiO2 chromatography and an appropriate gradient (CH3CN/MeOH/CH2Cl2) to afford 2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-4,5,6-triamine as a tan solid (89% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][NH:8][C:9]1[CH:18]=[C:17]([O:19]C)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[ClH:21]>>[ClH:21].[ClH:21].[NH2:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][NH:8][C:9]1[NH:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: COc1cc(NCC2CCCC2N)nc2ccccc12
Agent: Cl
Product: NC1CCCC1CNc1cc(=O)c2ccccc2[nH]1
Yield: 100 %

Procedure:
A solution of 2-[(2-aminocyclopentyl)methylamino]-4-methoxyquinoline (0.090 g, 0.332 mmol) in hydrochloric acid (10M, 5 ml) was stirred at reflux for 8 h. After cooling the mixture was concentrated to give the title compound as a light brown solid (50:50 mixture of cis and trans isomers; 0.11 g, 100%). δH (CD3OD) 1.45-2.80 (7H, m, (CH2)3, CHCH2NH), 3.40-3.95 (3H, m, CHNH2, CH2NH), 6.43-6.45 (1H, 2s, 3-H), 7.47-8.18 (4H, m, ArH). MS (ES+) 258 (M+H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[F:30][C:31]1[CH:51]=[CH:50][CH:49]=[C:48]([F:52])[C:32]=1[CH2:33][O:34][C:35]1[C:36]2[N:37]([C:41]([C:45](O)=[O:46])=[C:42]([CH3:44])[N:43]=2)[CH:38]=[CH:39][CH:40]=1.Cl.[NH2:54][CH2:55][CH:56]1[CH2:65][CH2:64][C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[N:57]1[C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67]>CN(C=O)C.O>[F:30][C:31]1[CH:51]=[CH:50][CH:49]=[C:48]([F:52])[C:32]=1[CH2:33][O:34][C:35]1[C:36]2[N:37]([C:41]([C:45]([NH:54][CH2:55][CH:56]3[CH2:65][CH2:64][C:63]4[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=4)[N:57]3[C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])=[O:46])=[C:42]([CH3:44])[N:43]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CCC1CN
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCC1CCc2ccccc2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
145 mg (0.45 mmol) of TBTU and 0.2 ml (1.89 mmol) of 4-methylmorpholine were added to 120 mg (0.38 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid Example 3A in 2.4 ml of DMF, and the mixture was stirred at RT for 10 min. 124 mg (0.42 mmol) of rac-tert-butyl 2-(aminomethyl)-3,4-dihydroquinoline-1(2H)-carboxylate hydrochloride were added and the reaction mixture was stirred at RT overnight. Water was added, and the reaction mixture was stirred at RT for 30 min. The precipitated solid was filtered off, washed with water and dried under high vacuum. This gave 190 mg (90% of theory; purity 100%) of the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15](O)=[O:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B.C1COCC1.[OH-].[Na+]>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N-BOC-2-(piperidin-4-yl)acetic acid (15.8 g) is dissolved in THF (150 ml) and 1M borane/THF (70 ml) is added dropwise. The solution is stirred at room temperature for about 20 hours and 1N sodium hydroxide solution (200 ml) is added dropwise. The THF is evaporated in vacuo and the aqueous residue extractred with ethyl acetate. The ethyl acetate solution is washed with water, dried over sodium sulfate, filtered, and evaporated in vacuo to give N-BOC-2-(piperidin-4-yl)ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([CH:13]=O)=[C:11]([I:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([CH:13]=[N:21][OH:22])=[C:11]([I:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)c(I)cc1OCc1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C=NO)c(I)cc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 100.8 %

Procedure:
A mixture of 4-benzyloxy-2-iodo-5-methoxybenzaldehyde (reference example 1-1) (12.2 g), hydroxylamine hydrochloride (2.54 g), sodium acetate (6 g) and ethanol (170 mL) was stirred at 70° C. for 1.5 hours. The mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The solid was collected by filtration to give the title compound (12.8 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:28])[CH3:29])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:37]4)=[O:34])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c6) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=2[F:32])[C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.CCN(C(C)C)C(C)C.Cl.[NH2:63][N:64]1[CH2:68][CH2:67][CH2:66][CH2:65]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH:63][N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)=[O:29])=[CH:25][C:24]=2[F:32])[C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NN1CCCC1
Reactant: O=C(O)c1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NN1CCCC1)c1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1

Procedure:
4-{[(4-Chloro-benzenesulfonyl)-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-amino]-methyl}-3-fluoro-benzoic acid (50 mg, 0.10 mmol) was dissolved in DMF (1 ml) and activated with the coupling reagent TPTU (33 mg, 0.11 mmol) and Hünig's base (0.03 ml, 0.26 mmol) for 2 min. 1-Aminopyrrolidine hydrochloride (0.013 g, 0.22 mmol) and further Hünig's base (0.03 ml, 0.26 mmol were added. After 1 h the reaction mixture was concentrated under reduced pressure and the residue taken up in ethyl acetate and washed with 5% KHSO4/10% K2SO4 (2×), water, brine, dried (MgSO4), filtered, concentrated under reduced pressure and purified over silica gel (ethyl acetate->ethyl acetate/5% MeOH) and the purified product was lyophilized: white lyophilisate 32 mg;
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].S(=O)(=O)(O)[OH:11]>O>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([NH2:9])=[O:11]
Reactant: O=S(=O)(O)O
Reactant: Cc1n[nH]c(N)c1C#N
Solvent: O
Product: Cc1n[nH]c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Amino-3-methyl-1H-pyrazole-4-carbonitrile (15.0 g, above) was added to stirred concentrated sulfuric acid (47 mL, 95%) cooled with cold water bath. After the addition, the reaction mixture was stirred at room temperature for 2 hours before it was poured with stirring into a mixture of ice and water. The precipitate was collected by filtration, washed with cold water to remove excess sulfuric acid, and dried in a vacuum desiccator to give 5-amino-3-methyl-1H-pyrazole-4-carboxylic acid amide. (Yield 19.6 g).
Reaction SMILES: [C:1](OC(OCC)OCC)(=O)C.[CH3:12][C:13]([NH:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]2[N:27]=[N:28][N:29]=[C:19]2[C:18]=1[NH2:30])([CH3:15])[CH3:14].[OH-].[Na+]>C(O)(=O)C>[CH3:15][C:13]([N:16]1[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]3[N:27]=[N:28][N:29]=[C:19]3[C:18]=2[N:30]=[CH:1]1)([CH3:12])[CH3:14]
Reactant: CC(C)(C)Nc1c(N)c2nnnn2c2ccccc12
Reactant: CCOC(OCC)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(C)n1cnc2c1c1ccccc1n1nnnc21

Procedure:
Diethoxymethyl acetate (1.9 mL) was added dropwise to a solution of N5-(1,1-dimethylethyl)tetrazolo[1,5-a]quinoline-4,5-diamine (1.5 g, 5.9 mmole, Example 19) in acetic acid (15 mL). The reaction mixture was heated on a steam bath for 1 hour then made basic with sodium hydroxide. The resulting precipitate was isolated by filtration then recrystallized from ethanol to provide 6-(1,1-dimethylethyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline, m.p. 224-226° C. Analysis: Calculated for C14H14N6: %C, 63.13; %H, 5.29; %N, 31.56; Found: %C, 62.90; %H, 5.44; %N, 31.52.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][C:10]=1[F:33])(C)(C)C.[ClH:35].O1CCOCC1>>[ClH:35].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][C:10]=1[F:33]
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CN)c(F)c1
Yield: 99 %

Procedure:
[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-carbamic acid tert-butyl ester from Example E98.1 (1.29 g, 2.8 mmol) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (1.1 g, 99%).
Reaction SMILES: [F:1][C:2]([F:23])([CH:21]=[CH2:22])[CH:3]([C:5]1[S:9][C:8]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)=[N:7][C:6]=1[CH3:20])[OH:4]>C(OCC)(=O)C.[Pd]>[F:23][C:2]([F:1])([CH2:21][CH3:22])[CH:3]([C:5]1[S:9][C:8]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)=[N:7][C:6]=1[CH3:20])[OH:4]
Reactant: C=CC(F)(F)C(O)c1sc(-c2ccc(C(F)(F)F)nc2)nc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(F)(F)C(O)c1sc(-c2ccc(C(F)(F)F)nc2)nc1C
Temperature: 25 °C
Yield: 97.4 %

Procedure:
500 mg 2,2-Difluoro-1-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-but-3-en-1-ol were dissolved in 50 ml ethyl acetate. 50 mg palladium (5% on charcoal) were added and the reaction mixture stirred at room temperature under a hydrogen atmosphere. After three hours the catalyst was filtered off and the filtrate evaporated in vacuo to obtain 490 mg 2,2-Difluoro-1-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-butan-1-ol as a white solid.