Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:4].O[NH:19][C:20](=[NH:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.ClCCl>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([C:20]2[N:19]=[C:3]([CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[O:4][N:29]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C1CCCCN1Cc1ccccn1
Reactant: COc1cccc(C(=N)NO)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cccc(-c2noc(C3CCCCN3Cc3ccccn3)n2)c1

Procedure:
1-Pyridin-2-ylmethyl-piperidine-2-carboxylic acid methyl ester (50 mg, 0.213 mmol) was mixed with N-hydroxy-3-methoxy-benzamidine (29 mg, 0.174 mmol) and sodium tert-butoxide (19 mg, 0.20 mmol) in toluene (0.5 mL) in a sealed vial at 130° C. for 10 min. The reaction mixture was cooled down and diluted with dichloromethane, washed with water. The title compound was purified by silica gel colomn chromatography with 20˜30% ethyl acetate in hexanes to give a colorless oil, 20 mg (32.7%). 1H NMR (CDCl3), δ(ppm): 8.50 (d, 1H), 7.66 (m, 3H), 7.47 (d, 1H), 7.38 (t, 1H), 7.13 (dd, 1H), 7.03 (dd, 1H), 4.11 (t, 1H), 3.88 (s, 3H), 3.73 (dd, 2H), 3.04 (m, 1H), 2.42 (m, 1H), 2.03 (m, 2H), 1.46-1.90 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][CH2:47][OH:48])[CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][CH2:47][O:48][S:59]([CH3:58])(=[O:61])=[O:60])[CH:44]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCCO)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCCOS(C)(=O)=O)c2)n1
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Intermediate 113e (163 mg, 0.25 mmol) in DCM (3 mL) was added DIPEA (174 μL, 1.0 mmol) followed by methanesulfonyl chloride (39 μL, 0.50 mmol). The reaction mixture was stirred for 1 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.12 min, m/z 731 [MH+].
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[NH:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)#[N:2].CC([O-])(C)C.[K+].Br[CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[C:8]2[NH:12][C:11](=[O:13])[N:10]([CH2:24][C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:9]2=[O:14])=[CH:15][CH:16]=1)#[N:2]
Reactant: N#Cc1ccc(C=C2NC(=O)NC2=O)cc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=C2NC(=O)N(CC(=O)OCc3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
6.4 g (0.03 mol) of (5-(4-cyanobenzylidene)-2,4-dioxoimidazolidine and 3.5 g (0.031 mol) of potassium tert-butylate are dissolved in 30 ml of dimethylformamide. After addition of 7.1 g (0.031 mol) of benzyl bromoacetate, the mixture is stirred at room temperature for 7 hours, heated briefly to 100° C. and concentrated. Water is added to the residue, and the mixture is extracted with ethyl acetate. The product crystallises out of the ethyl acetate phase, or can be precipitated by addition of heptane.
Reaction SMILES: C(OC([NH:8][S:9]([N:12]([CH3:50])[CH:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]([CH3:49])[C@@H:21]2[CH2:28][N:27]3[C:29]4[CH:30]=[C:31]([C:42]([OH:44])=[O:43])[CH:32]=[CH:33][C:34]=4[C:35]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)=[C:26]3[C:25]3[CH:45]=[CH:46][CH:47]=[CH:48][C:24]=3[O:23][CH2:22]2)[CH2:14]1)(=[O:11])=[O:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][S:9]([N:12]([CH3:50])[CH:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]([CH3:49])[C@@H:21]2[CH2:28][N:27]3[C:29]4[CH:30]=[C:31]([C:42]([OH:44])=[O:43])[CH:32]=[CH:33][C:34]=4[C:35]([CH:36]4[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]4)=[C:26]3[C:25]3[CH:45]=[CH:46][CH:47]=[CH:48][C:24]=3[O:23][CH2:22]2)[CH2:14]1)(=[O:11])=[O:10]
Reactant: CN(CCN1CCC(N(C)S(=O)(=O)NC(=O)OC(C)(C)C)C1)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCN1CCC(N(C)S(N)(=O)=O)C1)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Reaction time: 1 h

Procedure:
A solution of (7R)-7-[(2-{3-[{[(tert-butoxycarbonyl)amino]sulfonyl}(methyl)amino]pyrrolidin-1-yl}ethyl)(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid in DCM was treated with TFA and the solution was left stirring for 1 h. All volatiles were removed in vacuo to leave the product as pale yellow foam. (ES+) m/z 610 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)OC1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][N:27]1[C:23]([C:2]2[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)=[CH:24][CH:25]=[N:26]1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: O=C(O)c1ccc(Br)s1
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: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1ccc(C(=O)O)s1
Temperature: 80 °C

Procedure:
To a solution of 5-bromo-2-thiophenecarboxylic acid (100 mg, 0.48 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (267 mg, 1.93 mmol), tetrakistriphenylphosphine Pd(0) (28 mg, 24 umol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (94 mg, 0.48 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (˜100 mg, quant.): LC-MS (ES) m/z=209 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COc1ccc(N)cn1
Product: COc1ccc(Nc2nc(Cl)ncc2F)cn1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-amino-6-methoxypyridine gave 2-chloro-5-fluoro-N4-(6-methoxypyridin-3-yl)-4-pyrimidineamine. 1H NMR (CD3OD): δ 8.39 (d, 1H, J=3.0 Hz), 8.10 (d, 1H, J=3.6 Hz), 7.95 (dd, 1H, J=2.4 and 9 Hz), 8.30 (d, 1H, J=9 Hz), 3.91 (s, 3H); 19F NMR (CD3OD): −44737; LCMS: purity: 97%; MS (m/e): 255 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1)=[O:29].[CH:36]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH:36]1([NH:41][C:33]([C:30]2([C:28]([NH:27][C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)=[O:17])[CH:10]=4)=[CH:7][C:2]=3[F:1])=[O:29])[CH2:32][CH2:31]2)=[O:34])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)CC1
Reactant: NC1CCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)NC5CCCC5)CC4)c(F)c3)ccn2)CC1
Reaction time: 25 h
Yield: 51 %

Procedure:
To a solution of 1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylic acid (40 mg) in N,N-dimethylformamide (1.0 ml) were added cyclopentylamine (0.0163 ml), triethylamine (0.023 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (72.9 mg) at room temperature, followed by stirring for 25 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (23.2 mg, 51%).
Reaction SMILES: [C:1]1([CH:7]2[C:11]3([CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[O:10][C:9](=[O:17])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1.[H-].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[Cl:18][C:19]1[N:24]=[C:23]([N:8]2[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3([CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[O:10][C:9]2=[O:17])[CH:22]=[CH:21][N:20]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=C1NC(c2ccccc2)C2(CCOCC2)O1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1OC2(CCOCC2)C(c2ccccc2)N1c1ccnc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a mixture of 4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one (300 mg, 1.286 mmol) and 2,4-dichloropyrimidine (192 mg, 1.286 mmol) in DMF (7 mL) under argon was added NaH (60% wt., 67.9 mg, 2.83 mmol) in two portions. The mixture was stirred for ˜1 hour. The reaction mixture was carefully poured into ice-coiled 0.25N aqueous HCl solution. DCM and aqueous NaHCO3 solution were added. The separated aqueous layer was extracted with DCM (3×) and ethyl acetate (1×). The organic layers (DCM and ethyl acetate containing layers independently) were washed with brine, dried over Na2SO4 and filtered off. The organic layers were combined and concentrated under reduced pressure providing crude 3-(2-chloropyrimidin-4-yl)-4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one (330 mg) as a yellowish liquid, which was directly used in the next reaction without further purification. LCMS m/z 346.1 (M+H)+, Rt 0.83 min.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].Cl.[F:9][C@@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.C(N(CC)CC)C>CO>[F:9][C@@H:10]1[CH2:14][CH2:13][N:12]([C:4](=[O:6])[CH2:3][N+:1]#[C-:2])[CH2:11]1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: F[C@@H]1CCNC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: [C-]#[N+]CC(=O)N1CC[C@@H](F)C1
Yield: 77.2 %

Procedure:
To stirred and cooled (0° C.) methyl isocyanoacetate (96% technical grade, 0.79 g, 7.96 mmol) was slowly added (R)-(−)-3-fluoropyrrolidine hydrochloride (1.0 g, 7.96 mmol), triethylamine (1.11 mL, 7.96 mmol) and MeOH (2.5 mL). The mixture was stirred for 15 h at RT and concentrated. Water was added (50 mL) and the mixture was extracted with EtOAc (3×50 mL), dried over MgSO4, filtered and evaporated to obtained crude 1-((R)-3-fluoropyrrolidin-1-yl)-2-isocyanoethanone BLE 04170 as a brown oil (0.96 g, 77% yield) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](O)=[O:8])=[C:5]([CH3:10])[S:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:8][CH2:7][C:6]1[C:2]([CH3:1])=[N:3][S:4][C:5]=1[CH3:10]
Reactant: Cc1nsc(C)c1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nsc(C)c1CO

Procedure:
3,5-Dimethyl-4-isothiazolecarboxylic acid is converted to the methyl ester and the ester is reduced with lithium aluminum hydride in tetrahydrofuran to give 4-hydroxymethyl-3,5-dimethylisothiazole. Treating this hydroxymethyl compound with thionyl bromide gives 4-bromomethyl-3,5-dimethylisothiazole which is used as the starting material in the procedure of Example 121 to give N-cyano-N'-methyl-N"-[2-((3,5-dimethyl-4-isothiazolyl)methylthio)ethyl]guanidine.
Reaction SMILES: C1(S([C:10]2[N:11]=[N:12][C:13]([C:16]3[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)=[CH:14][CH:15]=2)(=O)=O)C=CC=CC=1.[OH-:31].[Na+].Cl>O1CCOCC1>[O:31]=[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)=[N:12][NH:11]1
Reactant: [OH-]
Reactant: O=S(=O)(c1ccccc1)c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 114.5 %

Procedure:
A mixture of 3-(3-phenylsulfonylpyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (20.0 g), sodium hydroxide solution (80 ml; containing 7.8 g of sodium hydroxide), and 1,4-dioxane (40 ml) was stirred for 2 hours under reflux. After being cooled to room temperature, the reaction mixture was acidified with 36% hydrochloric acid (15 ml). The precipitate formed was collected, washed with three 25 ml portions of water, and dried to give 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (16.0 g). An analytical sample was prepared by recrystallization from ethyl acetate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[C:14](B(O)O)=[CH:13][CH:12]=[CH:11][N:10]=1.Br[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[O:35][CH3:36])[C:22]#[N:23]>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>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([O:27][C:26]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[C:14]2[C:9]([O:8][CH3:7])=[N:10][CH:11]=[CH:12][CH:13]=2)=[C:29]([O:35][CH3:36])[CH:30]=1
Reactant: COc1ncccc1B(O)O
Reactant: COc1cc(Cl)ccc1Oc1ccc(C#N)cc1Br
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: COc1cc(Cl)ccc1Oc1ccc(C#N)cc1-c1cccnc1OC
Temperature: 70 °C
Yield: 86.1 %

Procedure:
Potassium carbonate (0.232 g, 1.68 mmol) and (2-methoxypyridin-3-yl)boronic acid (0.215 g, 1.26 mmol) were added to a solution of 3-bromo-4-(4-chloro-2-methoxyphenoxy)benzonitrile (Preparation 3, 0.284, 0.839 mmol) in dioxane (10 mL). The reaction was degassed three times, then tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.017 mmol) was added and the mixture was degassed three further times. The resulting mixture was heated at 70° C. over for 72 hours, then the reaction was cooled to room temperature. Then (2-methoxypyridin-3-yl)boronic acid (0.072 g, 0.42 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.017 mmol) were added and the reaction was heated at 90° C. for 3 hours. The reaction was allowed to cool to room temperature and the solvent removed in vacuo to give a black oil which was absorbed onto silica and purified by silica gel chromatography (Biotage®, SNAP cartridge 50 g, DCM 6CV then 99/1, DCM/MeOH 5 CV and then 9/1, DCM/MeOH 6 CV) to afford the title compound as a white solid (0.265 g).
Reaction SMILES: Cl[C:2]1[N:11]([CH3:12])[CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:19])[CH:8]=2)[N:3]=1.[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH2:24]>>[Cl:19][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:24][CH2:23][CH:22]([O:25][CH3:26])[O:21][CH3:20])[N:11]([CH3:12])[CH:10]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(CN)OC
Reactant: CN1C(Cl)=Nc2ccc(Cl)cc2C1c1ccccc1
Product: COC(CNC1=Nc2ccc(Cl)cc2C(c2ccccc2)N1C)OC
Temperature: 0 °C

Procedure:
The starting material may be prepared as follows: A mixture of 3.0 g of 2,6-dichloro-3,4-dihydro-3-methyl-4-phenylquinazoline and 15 ml of 2,2-dimethoxyethylamine was heated at 100°-110° C. for 1 hour. The mixture was poured into ice-water and the resulting mixture was extracted with ether. The ether layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The residual oil was crystallized from isopropyl ether-hexane to give 2.0 g of 6-chloro-3,4-dihydro-2-(2,2-dimethoxyethylamino)-3-methyl-4-phenylquinazoline as colorless needles, m.p. 104.5°-105° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([N:17]2[C@@:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([CH3:22])[C@@:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([CH3:30])[N:19]=[C:18]2[C:38]2[CH:39]=[N:40][C:41]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:42][C:43]=2[O:44][CH2:45][CH3:46])=[O:16])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[CH2:51]([N:53]=C=O)[CH3:52]>ClCCl>[CH2:51]([NH:53][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([N:17]2[C@@:21]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)([CH3:22])[C@@:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([CH3:30])[N:19]=[C:18]2[C:38]2[CH:39]=[N:40][C:41]([C:47]([CH3:50])([CH3:48])[CH3:49])=[CH:42][C:43]=2[O:44][CH2:45][CH3:46])=[O:16])[CH2:12][CH2:13]1)=[O:7])[CH3:52]
Reactant: CCN=C=O
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Product: CCNC(=O)N1CCC(NC(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
A mixture of (4S,5R)-2-(6-tert-butyl -4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carboxylic acid piperidin-4-yl amide (51.2 mg, 0.082 mmole, example 205) and ethyl isocyanate (12.0 mg, 0.169 mmole, Aldrich) in dichloromethane (4 mL) was stirred at room temperature for 2 h before concentrated to dryness. The residue was purified by flash column chromatography (silica gel, eluting with a gradient of 1-10% methanol in dichloromethane) to give the title compound (44.6 mg, 78% yield). HR-MS (ES, m/z) calculated for C37H47Cl2N6O3 [(M+H)+] 693.3081, observed 693.3081.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH2:12]([C:20]1[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:10][C:7]1[N:6]=[C:5]([NH2:11])[C:4]([CH2:3][N:23]2[CH2:22][CH:21]=[C:20]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:25][CH2:24]2)=[CH:9][N:8]=1
Reactant: C1=C(CCc2ccccc2)CCNC1
Reactant: Cc1ncc(CCl)c(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CC=C(CCc3ccccc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.8 %

Procedure:
A warm solution of 0.5 g (0.0026 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 40 ml of dimethylformamide was treated with 0.4 g (0.0021 mol) of 4-phenethyl-1,2,3,6-tetrahydro-pyridine and 0.9 ml (0.0064 mol) of triethylamine and the mixture was stirred at room temperature for 24 hours. The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water, extracted, chromatographed over silica gel with acetonitrile/ethanol 8:1 as the eluent and digested in diethyl ether. 0.18 g (22%) of 2-methyl-5-(4-phenethyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-pyrimidin-4-ylamine was obtained as white crystals; m.p. 152°-154°. A further 0.03 g of yellowish crystals was recovered from the mother liquor.
Reaction SMILES: [Br:1][C:2]([F:16])([F:15])[C:3]([F:14])([F:13])[S:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].F[B-](F)(F)F.[O:22]=[N+:23]=[O:24]>>[Br:1][C:2]([F:15])([F:16])[C:3]([F:13])([F:14])[S:4][C:5]1[C:6]([Cl:12])=[CH:7][C:8]([N+:23]([O-:24])=[O:22])=[CH:9][C:10]=1[Cl:11]
Reactant: O=[N+]=O
Reactant: FC(F)(Br)C(F)(F)Sc1c(Cl)cccc1Cl
Agent: F[B-](F)(F)F
Product: O=[N+]([O-])c1cc(Cl)c(SC(F)(F)C(F)(F)Br)c(Cl)c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 38.8 %

Procedure:
A stirred mixture of 30.5 g (0.085 mole) 2-(2-bromo-1,1,2,2-tetrafluoroethylthio)-1,3-dichlorobenzene and 13.3 g (0.10 mole) nitronium tetrafluoroborate (0.5M in sulfone) was heated at 100° C. for approximately 18 hours. An additional 4.0 g of nitronium tetrafluoroborate (solid) was added to the reaction mixture and heating was continued for 14 hours. The mixture was cooled and poured into 200 g of ice water. The resultant mixture was extracted with four 100 ml portions of methylene chloride and the extracts were combined. The organic extract was extracted with three 100 ml portions of a 2N sodium hydroxide solution. The basic aqueous extracts were combined and washed with 100 ml of methylene chloride. The washed extract was made acidic with concentrated hydrochloric acid while cooling in an ice bath. The acidic solution was saturated with sodium chloride and then was extracted with three 150 ml portions of methylene chloride. The organic extracts were combined and dried over anhydrous magnesium sulfate. After filtering the filtrate was evaporated under reduced pressure to leave an oil. This oil was subjected to column chromatography on silica gel, elution with n-heptane, to leave an oil after combining and evaporating the appropriate fractions. This oil was dissolved in n-heptane, leaving a small amount of solid which was removed by filtration. The filtrate was reduced in volume by evaporation under reduced pressure. An oil separated from the n-heptane solution and was removed by pipette. This oil (20.4 g) was found to be unreacted 1-(2-bromo-1,1,2,2-tetrafluoroethylthio)-2,6-dichlorobenzene. The remaining n-heptane was evaporated under reduced pressure to leave 13.3 g of 4-(2-bromo-1,1,2,2-tetrafluoroethylthio)-3,5-dichloronitrobenzene as an oil.
Reaction SMILES: I[C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:7](=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[CH:34])=[N:31][CH:32]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:2]3[CH:19]=[CH:18][C:5]4[N:6]([CH2:11][CH2:12][N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[C:7](=[O:10])[N:8]([CH3:9])[C:4]=4[CH:3]=3)=[N:31][CH:32]=2)=[CH:25][CH:26]=1
Reactant: Cn1c(=O)n(CCN2CCCC2)c2ccc(I)cc21
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Cn1c(=O)n(CCN2CCCC2)c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc21

Procedure:
Prepared according to general working method I from 5-iodo-3-methyl-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one (120 mg, 0.32 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (68 mg, 0.32 mmol).