Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Br[C:3]1C=[CH:7][C:6]([C:9]2N=CC(C(N)=N)=CN=2)=[CH:5][CH:4]=1.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:31]=[CH:30][C:29]([C:32]([NH2:34])=[NH:33])=[CH:28][N:27]=2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[N:27]=[CH:28][C:29]([C:32]3[N:34]=[CH:9][C:6]([CH2:5][CH2:4][CH3:3])=[CH:7][N:33]=3)=[CH:30][N:31]=2)=[CH:24][CH:25]=1
Reactant: N=C(N)c1cnc(-c2ccc(F)cc2)nc1
Reactant: N=C(N)c1cnc(-c2ccc(Br)cc2)nc1
Agent: Cl
Product: CCCc1cnc(-c2cnc(-c3ccc(F)cc3)nc2)nc1

Procedure:
Example 4 was repeated except that 2-(p-bromophenyl)-5-pyrimidinecarboxamidine hydrochloride and α-pentyl-62 -dimethylaminoacrolein in Example 4 were replaced by 2-(p-fluorophenyl)-5-pyrimidinecarboxamidine hydrochloride and α-propyl-62 -dimethylaminoacrolein, respectively, to obtain 2-(p-fluorophenyl)-5'-propyl-5,2'-bipyrimidinyl, which exhibited a C-N point of 199° C. and a N-I point of 203° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([O:13]C)[C:7]=2[CH2:6][CH:5]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:4]1.[BrH:22]>C(O)(=O)C>[BrH:22].[NH2:1][CH2:2][C@H:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([OH:13])[C:7]=2[CH2:6][C@@H:5]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:4]1
Reactant: COc1c(C)ccc2c1CC(C1CCCCC1)OC2CN
Agent: Br
Solvent: CC(=O)O
Product: Cc1ccc2c(c1O)C[C@@H](C1CCCCC1)O[C@H]2CN

Procedure:
A suspension of 1-aminomethyl-3-cyclohexyl-3,4-dihydro-5-methoxy-6-methyl-1H 2 benzopyran (467 mg, 1.43 mmol) in 10 mL of of glacial acetic acid and 10 mL of 48% hydrobromic acid was heated at reflux for 2 h. The reaction mixture was then concentrated in vacuo. The residue was crystallized from ethyl alcohol/methylene chloride to afford 478 mg of the title compound; m.p. 217°- 218° C.; MS DCl-NH3M/Z: 276 (M+H)+. Analysis calculated for C17H26BrNO2 : C, 52.71; H, 6.82; N, 3.51. Found: C, 52.85; H, 6.97; N, 3.90.
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[N:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.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>[Br:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][N:9]([CH3:11])[CH3:10])=[CH:6][N:7]=2)[CH:16]=[N:17][CH:18]=1
Reactant: OB(O)c1cncc(Br)c1
Reactant: CN(C)Cc1ccc(I)nc1
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: CCO
Solvent: COCCOC
Product: CN(C)Cc1ccc(-c2cncc(Br)c2)nc1

Procedure:
To a solution of (6-iodo-pyridin-3-ylmethyl)-dimethyl-amine (Intermediate 219) (1 eq, 3.89 mmol, 1.02 g) in DME/EtOH (1:1, 10 ml) are added 5-bromo-pyridine-3-boronic acid (Intermediate 100) (1.1 eq, 4.28 mmol, 0.864 g), Pd(PPh3)4 (0.05 eq, 0.195 mmol, 0.225 g), and aqueous Na2CO3 solution (4M, 3 eq, 11.7 mmol, 2.92 ml). The resulting mixture is heated using microwave radiation at 130° C. for 20 min. The mixture is filtered through a pad of Celite and concentrated under reduced pressure. 2M aqueous HCl is added, and the mixture is washed with DCM. The aqueous layer is adjusted to pH 11 using aqueous NaOH, and extracted with DCM. The organic layer is dried over MgSO4, and the solvents are removed in vacuo. The crude mixture is purified using reversed phase HPLC to give the title compound; [M+H]+=292/294.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:27][CH:23]5[CH2:24][NH:25][CH2:26][CH:22]5[CH2:21]4)[C:16]([CH3:28])=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1.[C:29]([CH2:31][C:32](O)=[O:33])#[N:30].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:27][CH:23]5[CH2:24][N:25]([C:32](=[O:33])[CH2:31][C:29]#[N:30])[CH2:26][CH:22]5[CH2:21]4)[C:16]([CH3:28])=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CC2CNCC2C1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CC2CN(C(=O)CC#N)CC2C1
Temperature: 45 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of N2-(2,3-dimethyl-2H-indazol-6-yl)-5-methyl-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (86.9 mg, 0.23 mmol) and 2-cyanoacetic acid (31.3 mg, 0.37 mmol) in a mixture of DCM (8 mL) and DMF (2 mL) were added HOAT (65.5 mg, 0.48 mmol) and EDCI (77.6 mg, 0.40 mmol). After addition, the reaction mixture was stirred at 45° C. for 1 h, and then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as a beige solid (69.8 mg, 68.2%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[C:19](=O)[CH2:18][CH2:17][C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].FC(F)(F)C1C=CC(B(O)[OH:31])=CC=1>>[F:10][C:8]([F:9])([F:11])[C:7]1[CH:2]=[CH:3][C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH:17]([OH:31])[C:16]=3[CH:15]=[N:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1CCc2cncc(-c3ccc(C(F)(F)F)c(F)c3)c21
Product: OC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Yield: 97 %

Procedure:
In analogy to the procedure described for the preparation of example 1 (rac)-4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (intermediate A-4 [C2]) was reacted with 4-(trifluoromethyl)phenylboronic acid to give the title compound as grey solid in 97% yield. MS: 280.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[NH:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([F:17])=[CH:11][N:10]=2)=[O:5])[CH3:2].[N:19]1([C:25]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[NH:8][C:9]2[C:14]([C:15]=1[N:22]1[CH2:23][CH2:24][N:19]([C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[O:26])[CH2:20][CH2:21]1)=[CH:13][C:12]([F:17])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cc(F)cnc2[nH]c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2[nH]c1=O

Procedure:
This compound was prepared from 4-chloro-6-fluoro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (78) and piperazine-1-yl-thiophene-2-yl-methanone according to general procedure E. Yield 3.16 g (66%), MP 124-133° C.; 1H-NMR (DMSO-d6): δ 1.26 (t, J=7.2 Hz, 3H), 3.11 (m, 4H), 3.88 (m, 4H), 4.28 (q, J=7.2 Hz, 2H), 7.15 (dd, J=3.6, 4.8 Hz, 1H), 7.45 (dd, J=1.2, 3.6 Hz, 1H), 7.79 (dd, J=1.2, 4.8 Hz, 1H), 8.05 (dd, J=2.8, 8.0 Hz, 1H), 8.63 (d, J=2.8 Hz, 1H) 12.40 (s, 1H); EIMS: 431 (M+1).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:55])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:54])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:53])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:52])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:51])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:50])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:49])[CH2:38][CH2:39][CH:40]=[C:41]([CH3:48])[CH2:42][CH2:43][CH:44]=[C:45]([CH3:47])[CH3:46])=[CH:7][CH2:8]O.N1C=CC=CC=1>CCCCCC>[Br:2][CH2:8][CH:7]=[C:6]([CH3:5])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:55])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:54])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:53])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:52])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:51])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:50])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:49])[CH2:38][CH2:39][CH:40]=[C:41]([CH3:48])[CH2:42][CH2:43][CH:44]=[C:45]([CH3:47])[CH3:46]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: BrP(Br)Br
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCBr
Temperature: 10 °C
Yield: 168.8 %

Procedure:
Under an atmosphere of argon, a solution of phosphorus tribromide (8.32 g, 30.7 mmol) in 27 ml of n-hexane was added in dropwise to a mixture of 3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecaen-1-ol (40 g, 57.3 mmol) and pyridine (1.92 ml, 23.8 mmol) in 587 ml of n-hexane at the temperature below 10° C. The solution was stirred at 10° C. for an hour, allowed to warm slowly from 10° to 20° C., stirred at 20°-25° C. for an hour and poured into cracked ice with stirring. The resulting precipitate was filtered off and the filtrate was extracted with n-hexane. The organic layer was washed with 5% sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness to afford 39.5 g (90.4%) of the desired compound, as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:18]([NH:21][NH2:22])(=O)[CH3:19]>C(O)CCC>[CH3:19][C:18]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:22][N:21]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3ccc(C(F)(F)F)cc3)nn12

Procedure:
A mixture of 4.50 g. of 3-chloro-6-(α,α,α-trifluoro-p-tolyl)pyridazine, 2.58 g. of acethydrazide and 100 ml. of n-butanol is heated at reflux temperature for 3 days. The solvent is removed and the resin dissolved in methylene chloride, passed through magnesol and the solid from the filtrate recrystallized from methylene chloride/hexane to afford the product as tan crystals, m.p. 199°-201° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[CH:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[H-].[Na+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[CH:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc2cccc(C)c2c1O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc2cccc(C)c2c1OCc1ccccc1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
5.5 g of 1'-hydroxy-8'-methyl-2'-acetonaphthone was dissolved in 50 ml of N,N-dimethylformamide, to which 1.7 g of 60% sodium hydride was added, followed by agitation at 50° C. for 10 minutes. The reaction solution was returned to room temperature, in which 5.5 ml of benzyl chloride was dropped, followed by heating again to 70° C. for reaction for 1 hour. After returning to room temperature, water was added to the solution, which was extracted with ethyl acetate. The resultant organic phase was washed with a saturated saline solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant reside was purified by silica gel column chromatography (15% ethyl acetate/hexane) to obtain 4.8 g of the captioned compound as a brown oily substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6]([CH3:7])[CH2:5][CH2:4][CH:3]1[CH:8]([CH3:11])[CH:9]=[O:10].[CH2:13](O)[C:14](=[CH2:16])[CH3:15].CC1C=CC(S(O)(=O)=O)=CC=1.O.C(O)C(=C)C>C1CCCCC1>[CH3:11][C:8]([CH:3]1[CH2:4][CH2:5][CH:6]([CH3:7])[C:2]1([CH3:1])[CH3:12])([CH2:15][C:14]([CH3:16])=[CH2:13])[CH:9]=[O:10]
Reactant: C=C(C)CO
Reactant: CC(C=O)C1CCC(C)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: C=C(C)CC(C)(C=O)C1CCC(C)C1(C)C

Procedure:
A 1 liter 3 neck flask equipped with a Dean-Stark trap, mechanical agitator, condenser, thermometer and nitrogen sweep was charged with the aldehyde from Example 28, 122.9 g at approximately 90% purity (0.66 mole), 230 g of methallyl alcohol (3.20 moles), 1.0 g of p-TSA, and 500 ml of cyclohexane. The contents were refluxed for 72 hours taking off a water-methallyl alcohol distillate (18 ml). The batch was cooled, washed with 250 ml of 10% sodium carbonate and 250 ml of brine. The mixture was dried, filtered, and concentrated in vacuo to afford 311 g of a mixture of acetal, and starting material. Distillation from 2 g of soda ash afforded 119 g of starting aldehyde. The pot residue 134.8 g contains the crude acetal (IR (Neat), 2980, 1660, 1470, 1150, 1100 cm-1) which was taken up in 200 ml of tetraglyme and 3 g of citric acid. Under nitrogen the flask was heated to 185° C. and 4 ml of methallyl alcohol were collected (approximately 2.5 hours). The flask was cooled and the contents were poured into 500 ml of 10% sodium carbonate and extracted with 2×200 ml of ether. The ether was washed with 200 ml of 10% sodium carbonate, 250 ml of water, and 250 ml of brine. The batch was dried, filtered, and concentrated to afford 124.7 g of crude product. Distillation afforded 58 g of purified product (40% yield). BP 2° C./0.3 mmHg; 1H-NMR (300 MHz), δ 0.64 (3H, s), 0.78 (3H, d, J=6.78 Hz), 0.91 (3H, s), 1.05 (3H, s), 1.60 (3H, s), 1.5-1.9 (6H, m), 2.3 (2H, AB quartet, JAB =13.8 Hz), 4.63 (1H, s), 4.81 (1H, s), 9.73 (1H, s); 13C-NMR (75 MHz), δ 13.50, 14.67, 16.73, 23.34, 24.23, 27.84, 28.88, 44.24, 45.95, 46.32, 53.13, 56.56, 115.46, 141.53, 207.14; IR (Neat), 2980, 2700, 1720, 1460, 900 cm-1 ; MS (m/e), 222 (M+), 207, 166, 123, 109, 95, 41 (Base);
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]1[CH2:7][CH:6]([OH:8])[CH2:5]1.[CH2:9]([O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23](F)=[C:24]([Cl:27])[CH:25]=2)[CH:20]=[CH:19][N:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(N(C)C)=O>[CH2:9]([O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:8][CH:6]3[CH2:7][CH:4]([NH2:3])[CH2:5]3)=[C:24]([Cl:27])[CH:25]=2)[CH:20]=[CH:19][N:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Fc1cc2ccnc(OCc3ccccc3)c2cc1Cl
Reactant: NC1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: NC1CC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)C1
Reaction time: 2 h
Yield: 30.5 %

Procedure:
To a suspension of 459 mg (11.5 mmol) of sodium hydride (60%) in 16 mL of dimethyl acetamide was added a solution of 333 mg (3.82 mmol) of 3-amino-cyclobutanol (50) in 8 ml of dimethyl acetamide. After stirring for 60 min at room temperature a solution of 1.00 g (3.48 mmol) of 1-benzyloxy-7-chloro-6-fluoro-isoquinoline (11) in 16 ml of dimethyl acetamide was added and stirring was continued first at room temperature, then for 2 h at 50° C. until the reaction went to completion. The reaction was quenched by addition of water and the reaction mixture was extracted three times with a mixture of dichloromethane and 2-propanol (3:1). The combined organic layers were evaporated, water was added and the crude product was subjected to lyophilization to remove remainders of dimethyl acetamide. The obtained crude product was purified by silica gel chromatography to yield 377 mg of the title compound (51) as a mixture of diastereoisomers. Rt=0.85 min (Method H). Detected mass: 355.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:9][CH2:10][C:11](=[CH2:13])C)([O:6][CH2:7][CH3:8])[CH3:5])[CH3:2].CC[O:16]C(C)=O>>[CH2:7]([O:6][C:4]([O:3][CH2:1][CH3:2])([O:9][CH2:10][C:11](=[O:16])[CH3:13])[CH3:5])[CH3:8]
Reactant: C=C(C)COC(C)(OCC)OCC
Reactant: CCOC(C)=O
Product: CCOC(C)(OCC)OCC(C)=O
Reaction time: 8 h
Yield: 82 %

Procedure:
To a cold (0 NC) suspension of NaH (2.68 g, 60%) in THF (150 mL) was added a solution of 1,1-diethoxyethanol [which was prepared according to the literature procedure of Zirkle, C. L. et. al. J. Org. Chem. 1961, 26, 395-407] (9.00 g) in THF (20 mL), and the reaction mixture was stirred at room temperature for 1 hour before adding methallyl chloride (8.0 mL). The reaction mixture was heated to reflux overnight, cooled and filtered through a plug of celite. Solvent was removed by rotary evaporation, and the residue purified by column chromatography (silica, 20% ether/hexane) to give 1,1-diethoxyethylmethallyl ether (11.5, 90%). Ozonolysis of a chilled (−30 NC) solution of this ether (6.00 g) in EtOAc (80 mL) was carried out until no starting material was detectable by TLC (1 hour). At this time, the reaction was purged with oxygen, treated with Pd(OH)2 (150 mg) and stirred under an atmosphere of hydrogen overnight. The catalyst was filtered away, and the filtrate was concentrated by rotary evaporation. The resulting residue was purified by column chromatography (silica, 20% EtOAc/hexane) to afford (1,1-diethoxyethoxy)acetone (4.53 g, 82%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[CH:8]3[CH2:19][CH:10]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([Br:18])=[CH:13][C:12]=4[C:6]2=[N:5][C:4]=1[C:20]([NH2:22])=[O:21])[CH2:9]3.[OH:23][C:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1>>[Br:18][C:14]1[C:15]([F:17])=[CH:16][C:11]2[CH:10]3[CH2:9][CH:8]([CH2:19]3)[N:7]3[C:3]([CH2:2][NH:1][C:27]([C:24]4([OH:23])[CH2:26][CH2:25]4)=[O:28])=[C:4]([C:20]([NH2:22])=[O:21])[N:5]=[C:6]3[C:12]=2[CH:13]=1
Reactant: NCc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: O=C(O)C1(O)CC1
Product: NC(=O)c1nc2n(c1CNC(=O)C1(O)CC1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
3-(aminomethyl)-10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 1-hydroxy-1-cyclopropane carboxylic acid similarly to as described in example 2 with non-critical modifications to afford crude 10-bromo-9-fluoro-3-((1-hydroxycyclopropanecarboxamido)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was reacted directly with 2-methyl-3-butyne-ol via General Procedure F to afford 13 mg (32%) of 9-fluoro-3-[[(1-hydroxycyclopropanecarbonyl)amino]methyl]-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=453.2.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)=[N:8][C:7]=2[CH:18]=1.[CH3:19][O:20][C:21](=[O:33])[CH2:22][C:23]1[C:24]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:25]=2[S:26][CH:27]=1>>[CH3:19][O:20][C:21](=[O:33])[CH2:22][C:23]1[C:24]2[CH:31]=[CH:30][C:29]([O:32][CH2:2][C:3]3[CH:4]=[CH:5][C:6]4[O:10][C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=5)=[N:8][C:7]=4[CH:18]=3)=[CH:28][C:25]=2[S:26][CH:27]=1
Reactant: COC(=O)Cc1csc2cc(O)ccc12
Reactant: Fc1cccc(-c2nc3cc(CCl)ccc3o2)c1
Product: COC(=O)Cc1csc2cc(OCc3ccc4oc(-c5cccc(F)c5)nc4c3)ccc12

Procedure:
Compound 69C and Compound 5C were reacted in a manner analogous to Compound 59A to give {6-[2-(3-Fluoro-phenyl)-benzooxazol-5-ylmethoxy]-benzo[b]thiophen-3-yl}-acetic acid methyl ester. This was reacted in a manner analogous to Compound 59 to give the title product. 400 MHz 1H NMR (DMSO-d6) δ ppm 3.7 (s, 2H) 5.3 (s, 2H) 7.1 (dd, J=8.8, 2.4 Hz, 1H) 7.3 (s, 1H) 7.5 (m, 1H) 7.5 (dd, J=8.3, 1.7 Hz, 1H) 7.6 (m, 3H) 7.8 (d, J=8.3 Hz, 1H) 7.9 (m, 2H) 8.0 (dt, J=8.1, 1.1 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1ccc(F)c(C(F)(F)F)c1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1

Procedure:
56 mg of pale yellow solid 3-{4-[3-(4-fluoro-3-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 4-fluoro-3-trifluoromethylphenyl isocyanate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[C:5]([NH2:11])=[C:4]([NH2:12])[C:3]=1[O:13][CH3:14].Cl.CO[C:18](=N)[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1>CO>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([CH:20]=[CH:19][C:18]2[NH:12][C:4]3[C:3]([O:13][CH3:14])=[C:2]([CH3:1])[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[C:5]=3[N:11]=2)[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: COC(=N)C=Cc1ccc(OC)c(OC)c1
Reactant: COc1c(C)c(C)c(OC)c(N)c1N
Agent: Cl
Solvent: CO
Product: COc1ccc(C=Cc2nc3c(OC)c(C)c(C)c(OC)c3[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
A mixture of 2,3-dimethyl-5,6-diamino-1,4-dimethoxybenzene (2.57 g; 10 mmol) and methyl-(3,4-dimethoxy)-cinnamoimidate hydrochloride (1.96 g; 10 mmol) in methanol (35 mL) was stirred at ambient temperature for 18 hours. The methanol solution was concentrated to 15 mL. The yellow precipitate was separated by filtration. Recrystallization from MeOH afforded 2.1 g (58% yield) of the title compound as yellow solid, m.p. 116-119° C. Anal. Calcd. for C21H24N2O4: C, 66.46, H, 6.57; N, 7.60. Found: C, 66.83; H, 6.64; N, 7.41. Mass spectrum: (EI,M+) m/z 368 1H-NMR (DMSO-d6; 400 MHz) δ12.4-12.5(broad s,1H), 7.6-7.4 (d, 1H), 7.2 (d, 1H), 7.07-7.16 (m, 2H), 7.0 (d, 1H), 3.84(s, 3H), 3.78 (s, 3H), 2.2 ppm (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:27]3[CH:28]=[CH:29][N:25]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)[N:26]=3)=[O:31])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1ccn(-c2ccncc2)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ccn(-c2ccncc2)n1
Yield: 83 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.058 g, 0.307 mmol), 1-(pyridin-4-yl)-1H-pyrazole-3-carboxylic acid (0.080 g, 0.307 mmol), DIPEA (0.160 ml, 0.921 mmol), HOBt hydrate (0.071 g, 0.460 mmol) and EDCI (0.088 g, 0.460 mmol) using the method of Example 274 affording 0.110 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.19 (d, 3H), 4.36 (m, 2H), 4.49 (m, 1H), 6.90 (d, 1H), 6.94 (d, 1H), 7.85 (d, 1H), 7.90 (m, 2H), 7.94 (m, 2H), 8.02 (s, 1H), 8.38 (d, 1H), 8.69 (m, 2H), 8.75 (d, 1H).