Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C1C=CC(N[C:12]2[N:13]=[C:14]([N:21]3[CH2:26][CH2:25][CH:24]([CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23][CH2:22]3)[C:15]3[O:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=CC=1)(=O)(=O)N.[Cl:36]C1N=C(Cl)C2OC=CC=2N=1.N1CCC(CNC(=O)OC(C)(C)C)CC1>>[Cl:36][C:12]1[N:13]=[C:14]([N:21]2[CH2:22][CH2:23][CH:24]([CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:32])[CH3:33])[CH2:25][CH2:26]2)[C:15]2[O:20][CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: Clc1nc(Cl)c2occc2n1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2nc(Nc3ccc(S(N)(=O)=O)cc3)nc3ccoc23)CC1
Agent: CC(C)(C)OC(=O)NCC1CCNCC1
Product: CC(C)(C)OC(=O)NCC1CCN(c2nc(Cl)nc3ccoc23)CC1

Procedure:
The precursor to Example #C.1, tert-butyl (1-(2-(4-sulfamoylphenylamino)furo[3,2-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate, was prepared as shown in Scheme B. 2,4-Dichlorofuro[3,2-d]pyrimidine [Ark Pharm] and tert-butyl piperidin-4-ylmethylcarbamate [Astatech] are reacted following conditions given in General Procedure A to give tert-butyl (1-(2-chlorofuro[3,2-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate. The intermediate is then reacted with 4-aminobenzenesulfonamide using the conditions described in General Procedure B to give the precursor to Example #C.1. The reaction sequence detailed above is translated in the preparations and examples section to “prepared using A from 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] with tert-butyl piperidin-4-ylmethylcarbamate [Astatech] and B with 4-aminobenzenesulfonamide.”
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[C:22](=[O:29])[NH:23][NH:24][C:25]=2[CH:26]([CH3:28])[CH3:27])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]([O:33][CH2:34][C@H:35]1[O:40][C@H:39](Br)[C@H:38]([O:42][C:43]([CH3:45])=[O:44])[C@@H:37]([O:46][C:47]([CH3:49])=[O:48])[C@H:36]1[O:50][C:51]([CH3:53])=[O:52])=[O:32].CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[C:43]([O:42][C@@H:38]1[C@@H:37]([O:46][C:47](=[O:48])[CH3:49])[C@@H:36]([O:50][C:51](=[O:52])[CH3:53])[C@@H:35]([CH2:34][O:33][C:31](=[O:32])[CH3:30])[O:40][C@H:39]1[O:29][C:22]1[C:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[CH:19][CH:18]=2)=[C:25]([CH:26]([CH3:27])[CH3:28])[NH:24][N:23]=1)(=[O:44])[CH3:45]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(OCCC(=O)OCc2ccccc2)cc1
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)OCc3ccccc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 12 using 4-({4-[2-(benzyl-oxycarbonyl)ethoxy]phenyl}methyl)-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-galactose instead of 4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)#[N:2].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:36][CH2:37][C:38]1[C:39]([OH:46])=[N:40][C:41]([CH3:45])=[CH:42][C:43]=1[CH3:44]>O.ClCCl>[C:1]([C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:36][CH2:37][C:38]2[C:39]([OH:46])=[N:40][C:41]([CH3:45])=[CH:42][C:43]=2[CH3:44])=[O:12])=[CH:13][CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1Oc1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3C#N)cc2)c(O)n1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
A mixture of 4-(2-cyanophenoxy)benzoic acid (500 mg, 2.09 mmol), 1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide hydrochloride (453 mg, 2.37 mmol), N-hydroxybenzotriazole (320 mg, 2.37 mmol), triethylamine (0.1 mL) and dichloromethane (5 mL) was stirred at 25° C. for half an hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (318 mg, 2.09 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 4-(2-cyanophenoxy)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide as a white solid (400 mg, 51%). LRMS (M+H+) m/z: calcd 373.14. found 373. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.38 (s, 1H), 7.94-7.91 (m, 3H), 7.69 (t, J=8.1 Hz, 1H), 7.37-7.31 (m, 1H), 7.16-7.06 (m, 3H), 5.86 (s, 1H), 4.29 (d, J=4.2 Hz, 2H), 2.17 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[N:17][CH:18]=1>>[Cl:12][C:13]1[CH:14]=[C:15]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:16]=[N:17][CH:18]=1
Reactant: Oc1cncc(Cl)c1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1cncc(Cl)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 5-chloropyridin-3-ol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH2:6][O:7][CH2:8][C:9]([O:11]C(C)(C)C)=[O:10].O[Li].O>C1COCC1.CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH2:6][O:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CC(C)(C)OC(=O)COCCc1cccc(Br)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of tert-butyl 2-(3-bromophenethoxy)acetate (580 mg, 1.84 mmol) in THF/CH3OH/H2O (8/4/4 mL) was added LiOH.H2O (232 mg, 5.5 mmol, 3.0 equiv.) at room temperature. The reaction mixture was stirred for 2 h at room temperature. After concentration under vacuum, the pH of the residual solution was adjusted to 2 with 1M hydrochloric acid. The carboxylic acid was extracted into EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford 2-(3-bromophenethoxy)acetic acid (470 mg, 99%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[C:4]([CH3:19])[CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:19][C:4]1[CH:3]=[C:2]([Cl:1])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)ccc1Oc1cccc2ccccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Oc2cccc3ccccc23)c(CBr)c1
Yield: 38.7 %

Procedure:
1-(4-Chloro-2-methylphenoxy)naphthalene (1.8 g) from Example 1 was dissolved in carbon tetrachloride (10 ml), followed by addition of NBS (1.2 g) and a catalytic amount of benzoyl peroxide under reflux for 2 hours. After leaving the solution to stand at room temperature, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ether=99:1) to give the title compound (900 mg; 39%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:23]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Cl:23][C:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc2[nH]ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: Nc1nc(Cl)c2cc[nH]c2n1
Temperature: 85 °C
Yield: 45.1 %

Procedure:
To a solution of 2-amino-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (5.00 g, 33.3 mmol), dimethylaniline (4.22 mL, 41.0 mmol) and benzyltriethylammonium chloride (15.2 g, 66.6 mmol) in acetonitrile (25 mL) at room temperature under argon was added POCl3 (18.6 mL, 200 mmol) dropwise for 30 min. The mixture was refluxed at 85° C. for 3 h and cooled to room temperature. The reaction was concentrated in vacuo to brown oil and to the oil was added an ice cold H2O (10 mL). The pH of the solution was adjusted to 5 by the addition of an aqueous NH4OH solution. Silica gel chromatography (CH2Cl2:MeOH=95:5) yielded 2.53 g (45%) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine as a light yellow solid. The product was then benzylated at N7 using standard techniques.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 101.5 %

Procedure:
(R)-1-Benzyl-3-hydroxypyrrolidine (3.9 g, 22 mmol) was dissolved in toluene (100 mL) and the solution stirred and cooled to 0°-5° C. Triethylamine (2.66 g, 26.2 mmol) was added followed by methanesulfonyl chloride (3.0 g, 26 mmol). A slurry formed after 30 minutes. The mixture was allowed to warm to room temperature and stirred overnight. Water (100 mL) was added to the reaction mixture and the organic layer separated and washed with water (100 mL) and concentrated under reduced pressure to give (R)-1-benzyl-3-mesyloxypyrrolidine (5.7 g) as a yellow oil: 1HNMR (CDCl3), 60 MHz): δ1.9-2.7 (m, 4H), 2.78 (d, 2H, J=15), 2.90 (s, 3H), 3.65 (s, 2H), 4.9-5.3 (m, 1H), 7.28 (s, 5H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH:13]=[CH2:14])=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH2:12]([O:11][C:10]1[CH:15]=[CH:16][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=1)[CH:13]=[CH2:14]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOc1ccc(N)cc1
Solvent: c1ccncc1
Product: C=CCOc1ccc(NS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Methanesulfonyl chloride (5.06 mL, 65.32 mmol) was added to a stirred solution of 3-[(4-amino)phenoxy]-1-propene (8.11 g, 54.43 mmol) in pyridine (80 mL) at 0° C. The mixture was stirred for 72 hours and was then poured slowly into ice-water and extracted with ether. The organic phase was washed with cold 1N HCl and was then extracted with 1N NaOH solution. The aqueous phase was acidified and the product (9.05 g, 73%) precipitated out as a white solid.
Reaction SMILES: C([Mg]Br)C.[CH3:5][CH:6]([CH2:9][CH3:10])[C:7]#[CH:8].[CH3:11][C:12]([CH3:22])([C:14](=[O:21])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[CH3:13].[Cl-].[NH4+]>C(OCC)C.ClCCl>[CH3:13][C:12]([CH3:22])([C:14]([OH:21])([C:8]#[C:7][CH:6]([CH3:5])[CH2:9][CH3:10])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[CH3:11]
Reactant: C#CC(C)CC
Reactant: CC(C)(C)C(=O)Cn1cncn1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(C)C#CC(O)(Cn1cncn1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
10 To a solution of ethyl magnesium bromide (20 ml) of a 3M solution in diethyl ether) in dry diethyl ether (30 ml) under N2 at room temperature was added a solution of 3-methyl-1-pentyne (5 g, 0.06 mol) in diethyl ether (20 ml). The resulting mixture was heated under reflux for 1 hour, and then cooled to 0° C. To this mixture was added slowly a solution of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butane-3-one (8.4 g, 0.05 mol) in dry dichloromethane (150 ml), and the mixture stirred for 45 minutes, a gelatinous precipitate formed. Ammonium chloride solution was added to the mixture, and the organic layer separated and washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica eluting with diethyl ether (20-100%) in petrol gave 2,2-dimethyl-3-hydroxy-3-(3-methyl-pent-1-yne-1-yl)-4-(1,2,4-triazol-1-yl)-butane) as a white solid (4.29 g) (mpt=59°-60° C.).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C-:13]#[N:14].[K+]>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[C:13]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:14]
Reactant: [C-]#N
Reactant: COC(=O)c1cccc(CBr)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.8 %

Procedure:
To a solution of methyl 3-(bromomethyl)benzoate (10.0 g, 44 mmol) in acetonitrile (100 mL) were added potassium cyanide (5.7 g, 87 mmol) and 18-crown-6 (1.0 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtrated, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→30/70). The combined solution was concentrated under reduced pressure to give the title compound (7.0 g, 91%) as a colorless oil.
Reaction SMILES: FC1C2C(C(=O)NC)=C(C3C=CC(F)=CC=3)OC=2C=CC=1C1C=C(C=CC=1C)C(O)=O.[CH3:32][C:33]1[N:34]=[CH:35][C:36]([C:39]2([NH2:42])CC2)=[N:37][CH:38]=1>>[CH3:32][C:33]1[N:34]=[CH:35][C:36]([C:39]#[N:42])=[N:37][CH:38]=1
Reactant: Cc1cnc(C2(N)CC2)cn1
Agent: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Product: Cc1cnc(C#N)cn1

Procedure:
This example was prepared from the coupling of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid with 1-(5-methylpyrazin-2-yl)cyclopropanamine (obtained from 5-methylpyrazine-2-carbonitrile by the reaction using Ti(OiPr)4/EtMgBr/BF3OEt2), and was isolated as a TFA salt after purification by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Sunfire Prep C18 19×100 5 um, Fraction Collection: 7.15-7.72 min. (UV detection at 220 nm). 1H NMR (500 MHz, CD3OD) δ 8.44 (s, 1H), 8.43 (s, 1H), 7.95 (m, 2H), 7.90 (dd, J=7.93, 1.83, 1H), 7.83 (s, 1H), 7.55 (d, J=8.55, 1H), 7.49 (d, J=7.93, 1H), 7.33 (d, J=8.24, 1H), 7.29 (t, J=8.85, 2H), 2.96 (s, 3H), 2.51 (s, 3H), 2.30 (s, 3H), 1.67 (m, 2H), 1.41 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=553.22, HPLC=1.647 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, =6.01 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=5.04 min. Analytical HPLC method: Solvent A=5% MeOH-95% H2O-10 mM NH4HCO3, Solvent B=95% MeOH-5% H2O-10 mM NH4HCO3, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, =10.24 min.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:13]=[C:14]([CH:22]([OH:25])[CH2:23][OH:24])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34].O>ClCCl>[F:10][C:11]([F:26])([F:27])[C:12]1[CH:13]=[C:14]([CH:22]([CH2:23][O:24][CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[OH:25])[CH:15]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:17]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: OCC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[Si](C)(C)CCOCOCC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.9 %

Procedure:
N-Ethyl-N,N-diisopropylamine (465 μl, 2.67 mmol) was added over 2 minutes, to a solution of (RS)-1-[3,5-bis(trifluoromethyl)phenyl]-1,2-ethanediol (Description 3, 488 mg, 1.78 mmol) and [2-(chloromethoxy)ethyl]trimethylsilane (315 μl, 1.78 mmol) in dichloromethane (3 mL) and the mixture was stirred at room temperature for 4 hours, then at 50° C. for 1 hour. The mixture was cooled and dichloromethane (20 mL) and water (20 mL) were added. The layers were separated and the aqueous layer was extracted with dichloromethane (10 mL). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (90:10) to give the title compound (352 mg, 49%). 1H NMR (400 MHz, CDCl3) δ 7.86 (2H, s), 7.79 (1H, s), 4.96 (1H, m), 4.73 (2H, s), 3.87 (1H, dd, J 11.1, 3.0 Hz), 3.73 (1H, br s), 3.61 (3H, m), 0.93 (2H, t, J 8.5 Hz), and 0.02 (9H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][N:7]1[CH2:16][C:15](=[O:17])[NH:14][C:8]1=[N:9]2.C(O)(=O)C.[Br:22]Br>O>[Br:22][C:13]1[C:4]([CH2:3][O:2][CH3:1])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]1[NH:14][C:15](=[O:17])[CH2:16][N:7]1[CH2:6]2
Reactant: BrBr
Reactant: COCc1cccc2c1CN1CC(=O)NC1=N2
Solvent: O
Solvent: CC(=O)O
Product: COCc1c(Br)ccc2c1CN1CC(=O)NC1=N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vigorously stirred solution of 1.87 g. (0.01 mole) of 6-methoxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one in 40 ml. of glacial acetic acid is added dropwise at room temperature 1.60 g. (0.01 mole) of bromine. The mixture is stirred at room temperature for one hour, water (50 ml.) is added and the volume concentrated (10-15 ml.) in vacuo. Additional water (50 ml.) is added, the solution made basic with ammonium hydroxice, warmed and the insoluble material filtered under suction. The colorless solid is washed with water, dried and crystallized from 50 ml. of 5% hydrochloric acid yielding the title product as a colorless solid. Purification is effected by crystallization from methanol/ether to yield the title product.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[C:14]([C:16]2[N:17]=[C:18]([CH3:28])[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:15])=[N:4][C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cu][C:36]#[N:37]>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[S:19][C:18]([CH3:28])=[N:17][C:16]=2[C:14]([N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][C:5]2[O:6][C:2]([C:36]#[N:37])=[C:3]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:4]=2)=[O:15])=[CH:22][CH:23]=1
Reactant: N#C[Cu]
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc(-c3ccccc3)c(Br)o2)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc(-c3ccccc3)c(C#N)o2)c(-c2ccc(F)cc2)s1
Yield: 13.5 %

Procedure:
The title compound (50 mg) was prepared by treating the compound of example 167 (0.410 g) with copper(I)cyanide (0.103 g) according to the method of example 96. Following column chromatography, further purification by HPLC was required (Supercosil ABZ+, 5-95% acetonitrile containing 0.1% trifluoroacetic acid-water containing 0.1% trifluoroacetic acid).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:4]=2[CH:3]=1.O.[NH2:24][NH2:25]>O1CCOCC1>[NH:24]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:4]=2[CH:3]=1)[NH2:25]
Reactant: NN
Reactant: O=C(CCCc1ccccc1)N1CCc2nnc(Cl)cc2C1
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc2c(nn1)CCN(C(=O)CCCc1ccccc1)C2

Procedure:
11.8 g of 3-chloro-5,6,7,8-tetrahydro-6-(4-phenylbutyryl)pyrido[4,3-c]pyridazine and 60 cc of hydrazine hydrate are stirred at a bath temperature of 50° for 53 hours with the addition of 50 cc of dioxane. The mixture is worked up as described in Example 10. The qentisinate of the title compound has a M.P. of 203°-205° (decomp., from methanol/water 2:1).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[CH:39]1(/[CH:45]=[CH:46]/B(O)O)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[NH2:30][C:29]1[S:28][C:27](/[CH:46]=[CH:45]/[CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: OB(O)/C=C/C1CCCCC1
Product: Cn1ncc(NC(=O)c2nc(/C=C/C3CCCCC3)sc2N)c1N1CCC(CN)CC1
Yield: 20 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and trans-(2-cyclohexylvinyl)boronic acid gave 257 as an off-white solid (17 mg, 20% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.70 (s, 1H), 7.36 (s, 2H), 7.31 (s, 1H), 6.40 (dd, J=16.0, 1.3 Hz, 1H), 6.20 (dd, J=16.0, 6.7 Hz, 1H), 3.63 (s, 3H), 3.10-2.96 (m, 6H), 2.47 (d, J=5.9 Hz, 2H), 2.21-2.10 (m, 1H), 1.83-1.71 (m, 7H), 1.35-1.13 (m, 8H). LCMS (ES+) m/z 444 (M+1)
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH:27]1([CH2:31][OH:32])[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:31][O:32][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCC1CCC1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCC3CCC3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (50 mg; 0.129 mmol), intermediate 42.1, and cyclobutanemethanol (44.8 mg; 0.515 mmol), example 56 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.Cl.N([O-])=O.[Na+].[I:32]I>CC(C)=O.O.CCOC(C)=O>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([I:32])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: II
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(I)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reaction time: 0.5 h

Procedure:
Compound 494 (0.62 g, 1.66 mmol) was dissolved in acetone (14 mL). Concentrated HCl (37%, 0.69 mL, 8.3 mmol) was added and the solution was cooled on an ice bath. NaNO2 (0.14 g, 1.99 mmol) was dissolved in H2O (1 mL) and added to the above solution during 15 minutes. The internal temperature was kept at 0° C.-2° C. during the addition. The suspension was stirred on an ice bath for 0.5 h, after which a solution of KI (0.41 g, 2.45 mmol) and I2 (0.31 g, 1.22 mmol) in H2O (4 mL) was added drop wise during 5 minutes. The mixture was stirred at 0° C. for 2 h. H2O (20 mL) and EtOAc (20 mL) was added and stirred and the phases were separated. The organic phase was washed with aqueous NaHSO3, then with aqueous Na2CO3, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:5 to afford the title compound as a slightly coloured crystalline compound.