Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH2:23]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccc2)n1
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(Nc2cc(C(F)(F)F)nc(-c3ccccc3)n2)cc1OC

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,4-dimethoxyaniline (44 mg, 0.290 mmol) similar to Example 75. The mixture was extracted with ethyl acetate (75 ml), washed with water (2×25 ml), washed with aqueous saturated NaCl (1×25 ml), and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness. The residual was purified by column chromatography and isolated as a yellow oil (35 mg, 48%). 1H NMR (CDCl3): 8.45-8.42 (m, 2H), 7.50-7.44 (m, 3H), 7.25 (s, 1H), 7.02 (s, 1H), 6.90 (s, 2H), 6.74 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H).
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Si:39]([O:46][C:47]1[C:54]([O:55][Si](C(C)(C)C)(C)C)=[C:53]([N+:63]([O-:65])=[O:64])[CH:52]=[CH:51][C:48]=1[CH:49]=O)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].C(OC)(C)(C)C>CCCCCC.C1COCC1.O>[N+:63]([C:53]1[C:54]([OH:55])=[C:47]([O:46][Si:39]([C:42]([CH3:44])([CH3:43])[CH3:45])([CH3:40])[CH3:41])[C:48](/[CH:49]=[CH:12]\[C:11]2[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:9]([O:8][CH3:7])[CH:10]=2)=[CH:51][CH:52]=1)([O-:65])=[O:64]
Reactant: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Reactant: CC(C)(C)[Si](C)(C)Oc1c(C=O)ccc([N+](=O)[O-])c1O[Si](C)(C)C(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: COc1cc(/C=C\c2ccc([N+](=O)[O-])c(O)c2O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
n-Butyllithium (1.6 mL of a 1.6 M solution in hexane, 2.6 mmol) was added dropwise to a suspension of 3,4,5-trimethoxybenzyltriphenylphosphonium bromide (1.1 g, 2.1 mmol) in THF (15 mL) at −20° C. The brick red solution was stirred at −20° C. for 30 min, cooled to −78° C., then a solution of 45 (0.88 g, 2.14 mmol) in THF (5 mL) was added dropwise. The reaction mixture was allowed to warm to rt overnight, then poured into t-BuOMe (ca. 20 mL) and water (ca. 20 mL), the layers were separated and the aqueous layer was re-extracted with t-BuOMe. The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated to dryness. Purification by column chromatography (SiO2, EtOAc:cyclohexane 1:1) gave 46 (0.355 g, 29%):
Reaction SMILES: [CH3:1][C:2]1[NH:7][CH:6]=[C:5]([C:8]([OH:10])=O)[C:4](=[O:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:56][S:57]([C:60]1[CH:67]=[CH:66][C:63]([CH2:64][NH2:65])=[CH:62][CH:61]=1)(=[O:59])=[O:58]>CN1C(=O)CCC1.CO.O>[CH3:56][S:57]([C:60]1[CH:67]=[CH:66][C:63]([CH2:64][NH:65][C:8]([C:5]2[C:4](=[O:11])[C:3]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:13]=3)=[C:2]([CH3:1])[NH:7][CH:6]=2)=[O:10])=[CH:62][CH:61]=1)(=[O:58])=[O:59]
Reactant: Cc1[nH]cc(C(=O)O)c(=O)c1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1[nH]cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid (preparation 1b, 3.00 g, 10.1 mmol), HBTU (4.00 g, 10.5 mmol) and DIPEA (5.00 mL, 29.4 mmol) in NMP (15 mL) is stirred for 30 min. Then, 4-methylsulfonylbenzylamine hydrochloride (2.46 g, 11.1 mmol) is added and the reaction mixture is stirred for 72 h at room temperature. Water is added to the reaction mixture. The formed gummy precipitate is dissolved in MeOH and purified by preparative reversed-phase HPLC (Gilson, XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 1.50 g (32% of theory); ESI mass spectrum: [M+H]+=465; Retention time HPLC: 0.89 min (Z003_001).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].CCN(CC)CC.[CH:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>CCOCC.CCOC(C)=O>[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:25]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:26])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: O=C(Cl)C1CCCC1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(NC(=O)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(Methanesulonyl)aniline hydrochloride (19 mmol) suspended in 25 mL of Et2O was added Et3N (48 mmol) and then a solution cyclopentanecarbonyl chloride (19 mmol) in 25 mL of Et2O was added dropwise during in 10 min. The reaction mixture was stirred for 3 h at RT and then diluted with EtOAc (100 mL) washed with 1N aq HCl, water and aq sat NaHCO3. The organic phase was dried and concentrated in vacuo to give crude cyclopentanecarboxylic acid (4-methanesulfonyl-phenyl)-amide which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][C:12]([C:14]3[N:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][C:4]=2[CH2:3]1.[C:20]1(O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.ClCCl>[CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([O:9][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[CH:10]=[CH:11][C:12]([C:14]3[N:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][C:4]=2[CH2:3]1
Reactant: Oc1ccccc1
Reactant: CN1CCC(O)c2ccc(-c3cccnn3)cc2C1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1CCC(Oc2ccccc2)c2ccc(-c3cccnn3)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
To a solution of (+)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ol (65 mg, 0.25) from Step A in THF (5 mL) was added phenol (73 mg, 0.77 mmol), tributylphosophine (156 mg, 0.77 mmol) and 1,1′-(azodicarboyl)dipiperidine (192 mg, 0.77 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane and washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (98:2 to 95:5 ethyl acetate/methanol), followed by HPLC to give (−)-2-methyl-5-phenoxy-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (52 mg, 62%) as a gum-like solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:15])[NH:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][C:2]1[C:3](=[O:15])[NH:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)[CH:7]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1cc(C2CCC(=O)CC2)c[nH]c1=O
Product: Cc1cc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c[nH]c1=O

Procedure:
The title compounds were prepared as white solids from the reductive amination of 3-methyl-5-(4-oxo-cyclohexyl)-1H-pyridin-2-one and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].CC(C)([O-])C.[K+].Cl[CH:21]([C:27]([CH3:29])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C=O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([O:13][CH:21]([C:27]([CH3:29])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: COc1cc(O)cc(OC)c1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Oc1cc(OC)c(OC)c(OC)c1)C(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,4,5-Trimethoxyphenol (5,83 g) was dissolved in DMF (60 mL), and potassium tert-butoxide (3.55 g) was added to the solution under ice cooling. Ethyl 2-chloroaceto-acetate (4.46 mL) was then added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was heated to 80° C. and stirred for 2 hours. After allowing the reaction mixture to cool, water was added to the reaction mixture to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane 1:3) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([OH:12])([CH3:11])[CH3:10])[C:4](=[O:13])[CH:3]=1.[CH3:14]I>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([O:12][CH3:14])([CH3:10])[CH3:11])[C:4](=[O:13])[CH:3]=1
Reactant: CC(C)(O)Cn1ccc(Br)cc1=O
Reactant: CI
Product: COC(C)(C)Cn1ccc(Br)cc1=O

Procedure:
The title compound was prepared from 4-bromo-1-(2-hydroxy-2-methyl-propyl)-1H-pyridin-2-one and methyl iodide following a procedure analogous to that described in Intermediate XXIX. Mass spectrum (ESI+): m/z=260/262 (Br) [M+H]+.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([Cl:30])=[C:11]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.N>ClCCl>[NH2:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:10]=1[Cl:30])[C:15]#[N:16]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(N)c(Cl)c(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
(I11B): To the stirred solution of tert-butyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)piperazine-1-carboxylate (2.0 g, 4.58 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (8.89 mL, 115 mmol) slowly drop wise at room temperature, stirred it for 3 hours at room temperature. On completion of the reaction, the reaction mixture was diluted with methylene chloride (300 mL), cooled it to 0° C., basified with ammonia solution and extracted twice, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material was washed with diethyl ether several times and dried under vacuum to get 3-amino-4-chloro-5-(piperazin-1-yl)benzonitrile (1.0 g) as a brown color solid. MS (ESI) m/z 237.5
Reaction SMILES: [Na+].[CH2:2]([C:6]1[S:10][C:9](OB(O)[O-])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:23]=2)=[CH:18][C:17]=1[F:35].C(=O)([O-])O.[Na+]>C1COCC1.O.CC(OC)(C)C.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>[CH2:2]([C:6]1[S:10][C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:23]=3)=[CH:18][C:17]=2[F:35])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(OB([O-])O)s1
Reactant: CCCCCCOc1ccc(-c2ccc(Br)c(F)c2)cc1
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: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(-c2ccc(-c3ccc(CCCC)s3)c(F)c2)cc1

Procedure:
A mixture of 4.48 g (20.0 mmol) of 5-butylthiophen-2-ylhydroxyboronic acid sodium salt, 7.0 g (19.9 mmol) of 4-bromo-3-fluoro-4′-hexyloxybiphenyl, 3.36 g (40.0 mmol) of sodium hydrogencarbonate and 1.1 g (0.95 mmol) of tetrakis(triphenylphosphine)palladium(0) in 90 ml of THF/water (2:1) is heated under reflux for 19 h. The mixture is diluted with MTBE, and the organic phase is separated off. The aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to completion, and the residue is purified by column chromatography (SiO2, n-heptane:toluene=9:1). The further purification is carried out by recrystallisation from ethanol. 2-Butyl-5-(3-fluoro-4′-hexyloxybiphenyl-4-yl)thiophene is obtained as a colourless wax having an m.p. of 66° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH2:11])[N:9]=2)[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCCl>[CH:20]1([NH:26][C:27]([NH:11][C:8]2[N:9]=[C:10]3[C:2]([CH3:1])=[CH:3][N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])[C:5]3=[N:6][CH:7]=2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C=NC1CCCCC1
Reactant: Cc1cn(COCC[Si](C)(C)C)c2ncc(N)nc12
Solvent: ClCCCl
Product: Cc1cn(COCC[Si](C)(C)C)c2ncc(NC(=O)NC3CCCCC3)nc12
Temperature: 25 °C
Yield: 64.1 %

Procedure:
7-Methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamine (41 mg, 0.147 mmol) was dissolved in 1,2-dichloroethane (1.5 mL). Cyclohexylisocyanate (0.19 mL, 1.47 mmol) was added and the reaction mixture was heated to reflux for 64 hr, cooled to RT, concentrated, purified by SiO2 chromatography (8 g SiO2, hexanes/EtOAc 0-50% EtOAc) to give 38 mg of 1-cyclohexyl-3-[7-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as a white solid (64% yield).
Reaction SMILES: CCCC[Sn]([O:14][Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])(CCCC)CCCC.[CH3:28][N:29]([CH3:34])[CH2:30][CH:31](O)[CH3:32].O>C1C=CC=CC=1>[CH2:24]([Sn:15]([O:14][CH:31]([CH3:32])[CH2:30][N:29]([CH3:34])[CH3:28])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Reactant: CC(O)CN(C)C
Solvent: c1ccccc1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)OC(C)CN(C)C

Procedure:
1-Dimethylamino-2-Propyl Tributylstannyl Ether is prepared from 89.4 gm (0.15 mole) bis(tributyltin) oxide and 30.9 gm (0.3 mole) 1-dimethylamino-2-propanol in 200 ml benzene. This is stirred and heated to reflux in a system that contains a Dean-Starke tube. After refluxing 23 hours a total of 2.6 ml of water (theory 2.7 ml) had collected in the Dean-Starke tube. The solvent is stripped off on a rotating evaporator to provide 111.0 gm of yellow liquid. This is fractionated at reduced pressure with collection at 167°-175° C. at 0.5 mm of 63.4 gm of straw colored liquid. (Percent yield - 54). Infrared spectral analysis shows this liquid to be the desired ether.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:39][C:40]1[C:41]([NH:58][CH:59]2[CH2:64][CH2:63][N:62]([CH:65]([CH3:69])[CH2:66][C:67]#[N:68])[CH2:61][CH2:60]2)=[C:42]2[CH:48]=[CH:47][N:46]([S:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)(=[O:51])=[O:50])[C:43]2=[N:44][CH:45]=1>CN(C=O)C.C(Cl)Cl>[C:52]1([S:49]([N:46]2[C:43]3=[N:44][CH:45]=[C:40]([NH:39][C:1](=[O:5])[CH2:2][CH3:3])[C:41]([NH:58][CH:59]4[CH2:60][CH2:61][N:62]([CH:65]([CH3:69])[CH2:66][C:67]#[N:68])[CH2:63][CH2:64]4)=[C:42]3[CH:48]=[CH:47]2)(=[O:50])=[O:51])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CC(CC#N)N1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(C(C)CC#N)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Propionic acid (0.0176 ml, 0.320 mmol), HATU (0.122 g, 0.320 mmol), and diisopropylethylamine (0.062 ml, 0.358 mmol) were added sequentially to a solution of 3-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-butyronitrile (0.134 g, 0.305 mmol) in a 4:1 mixture of CH2Cl2 and DMF (5 ml) at 25° C. The reaction mixture was stirred for 14 h at 25° C., then was partitioned between saturated NaHCO3 (4 ml) and CH2Cl2 (3 ml). The phases were separated using a phase separator column (Biotage) and the organic layer was concentrated under reduced pressure to afford crude N-{1-benzenesulfonyl-4-[1-(2-cyano-1-methyl-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionamide as a brown oil. LCMS (Method G, ESI): RT=0.60 min, m+H=495.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH2:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=1.[C:26]([C:28]1[CH:38]=[CH:37][C:31]([C:32]([N:34]=[C:35]=[O:36])=[O:33])=[CH:30][CH:29]=1)#[N:27].C(N(C(C)C)CC)(C)C>C(#N)C>[C:26]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:34][C:35](=[O:36])[NH:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=2)=[O:33])=[CH:37][CH:38]=1)#[N:27]
Reactant: N#Cc1ccc(C(=O)N=C=O)cc1
Reactant: CCOC(=O)COc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
In a similar manner to Example 1, starting material step (a), the p-toluenesulphonate salt of ethyl 4-aminophenoxyacetate (12.9 g, preparation described by Coutts, I. G. C. et al (1985), J. Chem. Soc. Perkin I, 1829), 4-cyanobenzoyl isocyanate (5.9 g), acetonitrile (400 ml total) and diisopropylethylamine (6.5 ml) were reacted to give, after stirring at ambient temperature for 1.5 hours, a solid, which was crystallised from acetonitrile/ethanol to give ethyl 4-[3-(4-cyanobenzoyl)ureido]phenoxyacetate (10.16 g) as an off-white solid: m.p. 200°-203° C.; NMR Spectrum (DMSO-d6) 1.22 (3H, t), 4.17 (2H, q), 4.75 (2H, s), 6.93 (2H, d), 7.49 (2H, d), 8.02 (2H, d), 8.13 (2H, d), 10.49 (1H, br s), 11.17 (1H, br s); Mass Spectrum m/Z 368 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:12])=[C:4]2[CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25].C(N(CC)C(C)C)(C)C.C(O)C>CO.ClCCl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:25][C:2]1[N:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:12])=[C:4]2[CH:3]=1
Reactant: O=C(NC1CCCCC1)c1cnn2cnc(Cl)cc12
Reactant: NCc1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(NC1CCCCC1)c1cnn2cnc(NCc3cccc(Cl)c3)cc12
Yield: 77 %

Procedure:
A solution of 5-chloro-N-cyclohexylpyrazolo[1,5-c]pyrimidine-3-carboxamide (28 mg, 0.09 mM, 1.0 equiv), 3-chlorobenzylamine (28 mg, 0.18 mM, 2.0 equiv), N,N-diisopropylethylamine (26 mg, 0.18 mM, 2.0 equiv) and 2 mL of ethanol were microwaved at 120° C. for 10 minutes. TLC (95:5 dichloromethane:methanol) showed reaction complete. The reaction mixture was cooled, the crystalline product collected by filtration, washed with cold ethanol and air dried to yield 29.7 mg (77%) of 5-(3-chlorobenzylamino)-N-cyclohexylpyrazolo[1,5-c]pyrimidine-3-carboxamide. LCMS (ESI) m+H=384.2; 1H NMR (400 MHz, DMSO-d6) δ: 8.61 (overlapping d and t, 2H), 8.06 (s, 1H), 7.60 (d, 1H), 7.4-7.25 (m, 4H), 6.49 (d, 1H), 3.70 (m, 1H), 1.75-1.5 (m, 5H), 1.4-0.8 (m, 5H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C@@H:20]3[CH2:22][C@H:21]3[CH2:23][OH:24])[C:14]=2[CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C@@H:20]3[CH2:22][C@H:21]3[CH:23]=[O:24])[C:14]=2[CH2:13][CH2:12]1
Reactant: OC[C@@H]1C[C@H]1c1cccc2c1CCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C[C@@H]1C[C@H]1c1cccc2c1CCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.2 %

Procedure:
DMSO (1.6 g, 21 mmol) was added to oxalyl chloride in CH2Cl2 (7.4 mL of 2M solution, 14.8 mmole) at -78° C. The (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)-cyclopropylmethanol (2.0 g, 10.5 mmol) in CH2Cl2 (15 mL) was added. The mixture was stirred for 20 min and then triethylamine (4.24 g, 42 mmol) was added. The mixture was warmed to room temperature and stirred for 30 min. The mixture was diluted with CH2Cl2 and washed with water, 1N HCl), and then 1N NaOH. The organic layer was dried and concentrated in vacuo to give the aldehyde product (1.98 g, 100%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.Cl[C:17]1[N:22]=[C:21]([C:23]([NH2:25])=[O:24])[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.CN(C)C=O>[NH2:25][C:23]([C:21]1[CH:20]=[CH:19][N:18]=[C:17]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:2]2)[N:22]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Reactant: NC(=O)c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CCCN(c2nccc(C(N)=O)n2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10 g (0.0467 mol) of 1,1-dimethylethyl [(piperidin-3-yl)methyl]carbamate, 7.5 g (0.0476 mol) of 2-chloropyrimidine-4-carboxamide, 9.7 g (0.07 mol) of potassium carbonate, 0.3 g of sodium iodide and 230 ml of N,N-dimethylformamide are introduced into a 1 liter, three-necked round bottom flask. The mixture is stirred for 24 hours at room temperature, under argon atmosphere, and is then poured into 500 ml of water. The mixture is extracted with dichloromethane, the organic phase is washed with water, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The crude crystalline product is taken up with petroleum ether and 15 g of white solid are obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Ca+2].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a solution of 3-acetoxyphenol (3.04 g, 20 ml) in dimethylformamide were added calcium carbonate (2.76 g, 20 mmol) and ethyl bromoacetate (2.2 ml, 20 mmol), and the mixture was stirred for 2 hours at room temperature. The reaction was quenched by water and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 10% aqueous citric acid solution, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution, and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified with silica gel chromatography (hexane:ethyl acetate=10:1) to give ethyl [3-(acetyloxy)phenoxy]acetate (3.30 g, 69%).