Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:25][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ncccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ncccn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 100 mg, 0.35 mmol) in methylene chloride (1 mL) was treated with 2 drops of dry N,N-dimethylformamide. The reaction mixture was cooled to 0° C. and then treated dropwise with oxalyl chloride (34 mL, 0.39 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in a small amount of methylene chloride and was slowly added to a cooled (0° C.) solution of 2-aminopyrimidine (67 mg, 0.70 mmol) in methylene chloride (1 mL). The resulting reaction mixture was stirred at 0° C. for 30 min and then stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo to remove methylene chloride. The resulting residue was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidin-2-yl-propionamide (85.4 mg, 67%) as a white solid: mp 103–105° C.; EI-HRMS m/e calcd for C18H19Cl2N3O (M+) 363.0905, found 363.0915.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([O:14]C)=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.BrC1C=CC(CN)=CC=1.N>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:25][C:12](=[O:14])[CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)[CH3:24])=[CH:19][CH:18]=1
Reactant: COC(=O)Cc1cccc2cnccc12
Reactant: CC(N)c1ccc(Br)cc1
Agent: N
Agent: NCc1ccc(Br)cc1
Product: CC(NC(=O)Cc1cccc2cnccc12)c1ccc(Br)cc1

Procedure:
The title compound was prepared using the procedure described in Example 132C using the product from Example 133B and 1-(4-bromophenyl)ethanamine instead of the product from Example 132B and 4-bromobenzylamine. 1H NMR (300 MHz, d6-DMSO) 9.81 (s, 1H), 9.00 (d, 1H), 8.70 (d, 1H), 8.48 (d, 1H), 8.40 (d, 1H), 8.04 (d, 1H), 7.92 (m, 1H), 7.51 (d, 2H), 7.23 (d, 2H), 4.84 (m, 1H), 4.10 (s, 2H), 1.35 (d, 3H). MS (DCI/NH3) m/e 369 (M+H)+; Anal. Calcd. For C19H17N2OBr.1.0HCl.1.0H2O: C, 53.86; H, 4.76; N, 6.61. Found: C, 53.47; H, 4.53; N, 6.76.
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:26]#[N:27])=[N:13][N:14]2[CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[CH:10][CH:9]=1.CO>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:26](=[NH:6])[NH2:27])=[N:13][N:14]2[CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:21])([F:23])[F:22])=[CH:10][CH:9]=1
Reactant: [NH4+]
Reactant: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2cc(Cl)ccc12
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CO
Product: N=C(N)c1nn(CCC(F)(F)C(F)(F)F)c2cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Trimethylaluminum (2.0M in toluene, 23.17 mL, 46.3 mmol) was added dropwise to a suspension of ammonium chloride (2.49 g, 46.5 mmol) in 69 mL toluene cooled to 0° C. The solution was then stirred at room temperature for 3 hours. This solution was then added to the intermediate from Step D (3.0 g, 9.27 mmol) and then heated at 110° C. for 6 hours. The solution was then cooled to room temperature and carefully poured to silica gel (ca 150 mL) and methanol (ca 250 mL). After stirring for 1.5 hours the suspension was filtered and the filtrate concentrated to give the indicated product which was used in the next step without further purification. 1H NMR (400 MHz, CH3 CN-d3): selected peaks δ 8.26 (d, J=8.7 Hz, 1H); 7.70 (d, J=1.7 Hz, 1H); 7.24 (dd, J=8.7, 1.8 Hz, 1H); 4.67 (t, J=7.1 Hz, 2H); 3.01-2.78 (m, 2H). m/z=341.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.[N-:25]=[N+:26]=[N-:27].[Na+].CN(C=O)C>O>[N:25]([C:7]1[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:20])([F:22])[F:21])[N:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+:26]=[N-:27]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1N=[N+]=[N-]
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A mixture of 15.13 g (0.040 mol) of product of Example 27, 2.85 g (0.040 mol) of sodium azide and 175 ml of DMF was stirred for 1 hour and poured into 500 ml of water. The mixture was extracted with ether. The ether was extract was washed several times with water, dried (MgSO4) and concentrated to give 14.4 g (93.7%) of product; mp 46°-47° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:7])[CH2:5][OH:6].CO[C:19](OC)([CH3:21])[CH3:20].B(F)(F)F.O(CC)CC>CC(C)=O>[CH3:1][O:2][C:3]([C:4]1([CH3:7])[CH2:5][O:6][C:19]([CH3:21])([CH3:20])[N:8]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:16]
Reactant: COC(=O)C(C)(CO)NC(=O)OC(C)(C)C
Reactant: COC(C)(C)OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(C)=O
Product: COC(=O)C1(C)COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a stirring solution of 3 (9.342 g, 40 mmol) in acetone (115 mL) in a flame dried round bottom flask under an inert atmosphere was added 2,2-dimethoxypropane (66 mL). To this solution was added BF3-OEt2 (0.30 mL, cat) and stirring was continued at rt for 2 h. The reaction mixture was then concentrated in vacuo to an orange oil which was purified by flash chromatography to provide 4 (9.392 g, 85%) as a white solid. Rf=0.55 (1:3 EtOAc/hexanes). Compound was observed as an uneven mixture of rotomers.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)[CH:10]([OH:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)[CH:10]([O:28][CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CN(Cc2ccccc2)CCC1c1cccc(OCc2ccccc2)c1
Reactant: BrCc1ccc2ccccc2c1
Product: c1ccc(COc2cccc(C3CCN(Cc4ccccc4)CC3OCc3ccc4ccccc4c3)c2)cc1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating (3RS,4RS)-1-benzyl-4-(3-benzyloxy-phenyl)-piperidin-3-ol with 2-bromomethylnaphthalene there was obtained (3RS,4RS)-1-benzyl-4-(3-benzyloxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a colourless resin; MS: 514 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=[O:14])[CH2:12][CH3:13])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:15](=O)([O:18]C)[O:16][CH3:17].[H-].[Na+].C(O)(=O)C>O>[CH3:13][CH:12]([C:11]([C:10]1[C:2]([CH3:1])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12)=[O:14])[C:15]([O:16][CH3:17])=[O:18]
Reactant: COC(=O)OC
Reactant: CCC(=O)c1c(C)nn2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(C)C(=O)c1c(C)nn2ccccc12

Procedure:
2-Methyl-3-propionylpyrazolo[1,5-a]pyridine (5.28 g) was dissolved into dimethyl carbonate (100 ml), and, after adding sodium hydride (3.37 g), the mixture was refluxed for 8 hours under heat. Under cooling in water bath, acetic acid was added, then, following dilution with water, the mixture was extracted with methylene chloride. After the organic layer was dried over anhydrous sodium sulfate, solvent was distilled off under reduced pressure and the residue was purified by means of silica gel column chromatography (developing solvent, ethyl acetate:n-hexane=1:3˜1:1) to obtain aimed product (5.13 g) as a yellow oily product.
Reaction SMILES: C(O[CH:4]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N+:6]([O-:8])=[O:7])C.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.C(O)C>C1(C)C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH:4]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N+:6]([O-:8])=[O:7])=[N:16][CH:17]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC=C(C(=O)OCC)[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(Br)cn1)[N+](=O)[O-]
Yield: 63.2 %

Procedure:
A mixture of 2-ethoxy-1-ethoxycarbonyl-1-nitroethene (5.7 g) and 2-amino-5-bromopyridine (5.2 g) in toluene was heated at reflux with slow removal of the ethanol formed during 2 hours. The reaction mixture was cooled and concentrated in vacuo to give a yellow powder which was triturated with hot ethanol, to give 2-(5-bromopyrid-2-ylamino)-1-ethoxycarbonyl-1-nitroethene (6.0 g) in the form of a pale yellow powder, m.p. 141°-142° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:3]=1.[NH2:26][CH2:27][CH:28]([OH:31])[CH2:29][OH:30]>O1CCOCC1.CN1CCCC1=O>[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:9]=1[CH2:8][C:6]1[N:7]=[C:2]([NH:26][CH2:27][CH:28]([OH:31])[CH2:29][OH:30])[N:3]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:5]=1
Reactant: N#Cc1ccc(Nc2nc(Cl)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Reactant: NCC(O)CO
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: N#Cc1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)nc(NCC(O)CO)n2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.2 %

Procedure:
A mixture of intermediate (27) (0.00256 mol) and 3-amino-1,2-propanediol (0.00563 mol) in 1,4-dioxane (10 ml) and 1-methyl-pyrrolidinone (2 ml) was stirred at RT for 48 hours under argon. The reaction mixture was concentrated, quenched with DCM/H2O and stirred. The precipitate was filtered off, yielding 1.12 g (86.9%) of (±)-4-[[4-[(2,6-dichlorophenyl)methyl]-6-[(2,3-dihydroxypropyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile (compound 26).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH2:13][CH3:14].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18][N:30]1[CH2:29][CH2:28][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=2)[CH2:32][CH2:31]1)[CH2:13][CH3:14]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCC1(CCCCCl)C(=O)Nc2c(Cl)cc(Cl)cc21
Product: CCC1(CCCCN2CCN(c3cccc(Cl)c3)CC2)C(=O)Nc2c(Cl)cc(Cl)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 5,7-dichloro-3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(3-chloro-phenyl)-piperazine.
Reaction SMILES: [S:1]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)([O:4][CH2:5][C@H:6]([OH:17])[C@H:7]([CH3:16])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])=[O:2].C(N(CC)CC)C.[Si:32](OS(C(F)(F)F)(=O)=O)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>C(Cl)Cl>[S:1]([C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=1)([O:4][CH2:5][C@H:6]([O:17][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C@H:7]([CH3:16])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)[C@H](C)CCc2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)CCc2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
A solution of tosylate 18 (100 g, 0.29 mol) and triethylamine (81.0 mL, 0.58 mol) in CH2Cl2 (1200 mL) was treated with neat TBS-OTf (99 mL, 0.43 mol) dropwise with continued stirring for another 20 min. The reaction was washed twice with brine, dried over MgSO4 and concentrated to dryness. The oil was dissolved in a minimal amount of hexanes and filtered over a silica pad, eluting with hexanes:EtOAc (9:1) to yield the title compound as a slightly amber oil, 134 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:9]5[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][C:8]=5[N:7]([CH3:22])[C:6]=4[N:23]=3)[C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CCC2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 84.1 %

Procedure:
tert-Butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (110 mg, 0.289 mmol) and 4-(4-chlorobenzyloxy)pyridin-2(1H)-one (75 mg, 0.318 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (130 mg, 84%) as a colorless oil: ESI MS m/z 535 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:11][CH:10]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1nccs1
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: C1COCCO1
Product: COc1ccc(-c2nccs2)cc1
Yield: 47.1 %

Procedure:
A mixture of 2-bromothiazole (2.0 g, 12.2 mmol), (4-methoxyphenyl)boronic acid (1.9 g, 12.8 mmol), K2CO3 (5.0 g, 36.5 mmol) and (Ph3P)4Pd (0.7 g, 0.61 mmol) in dioxane (40 mL) was refluxed for 16 h. After the solids were filtered off, the filtrate was concentrated in vacuo. The residue was purified by a column chromatography on silica gel to yield the title compound (1.1 g, 50%). 1HNMR (400 MHz, CDCl3) δ 3.86 (s, 3H), 6.96 (d, J=8.8 Hz, 2H), 7.25 (d, J=3.2 Hz, 1H), 7.81 (d, J=3.2 Hz, 1H), 7.90 (d, J=8.8 Hz, 2H), MS m/z 192 (M+1).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27](C3CCCCO3)[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:34])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:34][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)[C:14]([CH3:16])=[CH:15][C:10]=1[S:7]([NH:6][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCC[C@@H]3c3ccnn3C3CCCCO3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCC[C@@H]1c1ccn[nH]1
Yield: 108.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentyl}oxy)benzenesulfonamide (155 mg, 0.238 mmol) prepared in Example 138b, triethylsilane (0.30 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield the title compound (108 mg, 99%) as a colorless solid.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:14]1[C:15]([CH3:24])=[C:16]([CH3:23])[C:17]2[N:18]([CH:20]=[CH:21][N:22]=2)[N:19]=1>CN(C)C=O>[CH3:24][C:15]1[C:14]([O:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7](=[O:9])(=[O:8])[NH2:10])=[N:19][N:18]2[CH:20]=[CH:21][N:22]=[C:17]2[C:16]=1[CH3:23]
Reactant: CC(C)(CO)CS(N)(=O)=O
Reactant: Cc1c(Cl)nn2ccnc2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(OCC(C)(C)CS(N)(=O)=O)nn2ccnc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
0.59 g of 60% oily sodium hydride was suspended in 21 ml of dimethylformamide. To this suspension, 1.18 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide was added, followed by stirring at room temperature (15° to 20° C.) under reduced pressure for 1 hour. To this mixture was added 1.28 g of 6-chloro-7,8-dimethylimidazo[1,2-b]pyridazine, followed by stirring at 60° C. for 40 minutes. After dimethylformamide was distilled off under reduced pressure, ice water was added to the residue, which was subsequently adjusted to pH 6 by the addition of 5 N hydrochloric acid andthen extracted with ethyl acetate-tetrahydrofuran (2:1). The extract was washed with 20 ml of saturated saline and then dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate-methanol (10:10:1). The fraction containing the desired product was concentrated and recrystallized from ethanol to yield 0.866 g of the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH3:42])[CH2:3][O:4][C@@H:5]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([NH:14][C@@H:15]([CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:16][N:17]([CH3:27])[C:18](=[O:26])[O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:13])[CH2:7]1.CCN(C(C)C)C(C)C.Cl[C:53]([O:55][CH3:56])=[O:54]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:56][O:55][C:53]([NH:1][CH:2]([CH3:42])[CH2:3][O:4][C@@H:5]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([NH:14][C@@H:15]([CH2:28][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:16][N:17]([CH3:27])[C:18](=[O:26])[O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:13])[CH2:7]1)=[O:54]
Reactant: COC(=O)Cl
Reactant: CC(N)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of crude 2-(trimethylsilyl)ethyl (2S)-2-((3R)-3-((1R)-(2-aminopropoxy)(3-chlorophenyl)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate (0.1340 g), obtained as, described above, DMAP (0.151 g), DIPEA (2 mL), and methyl chloroformate (0.483 g) in CH2Cl2 was stirred at rt for 2 d. After the reaction mixture was evaporated under reduced pressure, the crude product was purified by reversed-phase HPLC to give 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((R)-(2-(methoxycarbonylamino)propoxy)(3-chlorophenyl)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate. MS ESI +ve m/z 705 (M+Na).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[CH2:12](Cl)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>CC#N>[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: Cc1[nH]c2ncccc2c1C
Reactant: O=C(CCl)c1ccccc1
Solvent: CC#N
Product: Cc1nc2n(CC(=O)c3ccccc3)cccc-2c1C

Procedure:
A solution of 2,3-dimethylpyrrolo[2,3-b]pyridine (146 mg, 1 mmol) and phenacyl chloride (170 mg, 1.1 mmol) in 3 ml CH3CN was refluxed for 4.5 h. The mixture was allowed to cool and the precipitated product filtered off and washed with a small volume of ice cold CCl4 affording 207 mg (69%) pure title compound as the hydrochloride salt.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[C:4]([O:13][CH:14]([CH3:16])[CH3:15])[CH:3]=1.[CH3:17][O:18][CH2:19][CH2:20][OH:21]>>[CH:14]([O:13][C:4]1[CH:3]=[C:2]([O:21][CH2:20][CH2:19][O:18][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6](=[O:12])[NH:7][CH:8]=[N:9]2)([CH3:16])[CH3:15]
Reactant: COCCO
Reactant: CC(C)Oc1cc(F)cc2nc[nH]c(=O)c12
Product: COCCOc1cc(OC(C)C)c2c(=O)[nH]cnc2c1
Temperature: 120 °C
Yield: 27.8 %

Procedure:
An analogous reaction to that described in example 137b, but starting with 7-fluoro-5-isopropoxyquinazolin-4(3H)-one (444 mg, 2 mmol) and 2-methoxyethanol (0.32 ml, 4.06 mmol) and heating at 120° C. for 1.5 hours yielded 5-isopropoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one (155 mg, 28% yield) as a beige solid:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.[O:29]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30]1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[C:5]([C:25]([NH:34][C@H:31]2[CH2:32][CH2:33][O:29][CH2:30]2)=[O:26])[CH:4]=[N:3]1
Reactant: N[C@H]1CCOC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N[C@H]2CCOC2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reaction time: 0.33 h
Yield: 99.1 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), (S)-tetrahydrofuran-3-ylamine hydrochloride (68.2 mg, 552 μmol), diisopropylethylamine (193 μl, 1.1 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is refluxed for 18 hours. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording (S)-1-methyl-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N4-(tetrahydrofuran-3-yl)-1H-pyrazole-4,5-dicarboxamide (118 mg, 99.1%) as a white solid. mp.: >250° C. MS: m/z=432.4 (M+H+).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][N:12]([CH2:20][CH2:21][CH:22]([OH:27])[C:23]([F:26])([F:25])[F:24])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:15]([O:14][C:13](=[O:19])[N:12]([CH2:20][CH2:21][CH:22]([O:27][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]([CH3:10])[N:9]=1)[C:23]([F:26])([F:25])[F:24])[CH3:11])([CH3:18])([CH3:16])[CH3:17]
Reactant: CN(CCC(O)C(F)(F)F)C(=O)OC(C)(C)C
Reactant: Cc1ccc(C#N)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C#N)c(OC(CCN(C)C(=O)OC(C)(C)C)C(F)(F)F)n1
Reaction time: 96 h
Yield: 31.2 %

Procedure:
A mixture of 2-chloro-6-methylnicotinonitrile (0.215 g, 1.41 mmol) and tert-butyl N-methyl-N-(4,4,4-trifluoro-3-hydroxybutyl)carbamate (0.345 g, 1.34 mmol) in DMF (6 mL) was treated with caesium carbonate (0.875 g, 2.69 mmol) at ambient temperature. After stirring for 4 days, the mixture was diluted with water and extracted with diethyl ether. The combined organic extracts were washed (water, brine), dried, and evaporated to an orange oil/solid mixture. The crude material was purified by silica gel chromatography, eluting with 100% dichloromethane and 5% methanol/95% dichloromethane (v/v) to give the product as a yellow oil (0.156 g, 31%).