Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:44][CH3:45])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:21]1[CH2:38][CH:37]2[N:23]([C:24](=[O:43])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]3[C:34]([C:40](O)=[O:41])([NH:35][C:36]2=[O:39])[CH2:33]3)[CH2:22]1.[CH3:46][C:47]1([S:50]([NH2:53])(=[O:52])=[O:51])[CH2:49][CH2:48]1.C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C(NS(C6CC6)(=O)=O)=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Cl:1][C:2]1[C:3]([O:44][CH3:45])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:21]1[CH2:38][CH:37]2[N:23]([C:24](=[O:43])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]3[C:34]([C:40]([NH:53][S:50]([C:47]4([CH3:46])[CH2:49][CH2:48]4)(=[O:52])=[O:51])=[O:41])([NH:35][C:36]2=[O:39])[CH2:33]3)[CH2:22]1
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6(C)CC6)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl

Procedure:
The title compound was prepared from 17-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-2,14-dioxo-3,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (56) and 1-methylcyclopropylsulfonamide following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl]-(cyclopropyl)sulfonamide 11: m/z=770 (M+H)+. 1H NMR (CDCl3): 0.90-0.98 (m, 1H), 1.05-2.0 (m, 2H), 1.3-1.4 (d, J=6.9 Hz, 6H), 1.45-1.55 (m, 2H), 1.5 (s, 3H), 1.55-1.7 (m, 2H), 1.75-1.9 (m, 2H), 1.9-2.1 (m, 2H), 2.1-2.4 (m, 2H), 2.4-2.5 (m, 2H), 2.6-2.7 (m, 2H), 3-3.1 (m, 1H), 3.15-3.25 (m, 1H), 3.3-3.4 (m, 1H), 3.6-3.7 (m, 1H), 3.9 (d, J=11.6 Hz, 1H), 4.05 (s, 3H), 4.6 (t, J=8.0 Hz, 1H), 5.2 (t, J=10.6 Hz, 1H), 5.5 (br s, 1H), 5.6-5.7 (m, 1H), 6.9 (br s, 1H), 7.1 (s, 1H), 7.2 (d, J=9.3 Hz, 1H), 7.53 (s, 1H), 7.95 (d, J=9.3 Hz, 1H), 10.8 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15](O)=[O:16])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][N:8]3[C:7](=[O:20])[C:6]=2[CH:21]=1.C(N1C=CN=C1)([N:24]1C=CN=C1)=O.C(=O)=O.N>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([NH2:24])=[O:16])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][N:8]3[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(Cl)ccc1-2
Agent: N
Agent: O=C=O
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(Cl)ccc1-2
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
3.04 g (10.0 mmol) of (S)-7-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid were suspended in 15 ml of N,N-dimethylformamide and treated portionwise at room temperature with 1.78 g (11.0 mmol) of 1,1'-carbonyldiimidazole. After the CO2 evolution had finished the clear brown solution was stirred at 50° for 30 min., cooled and treated dropwise at a temperature below 25° within about 10 min. with 2.5 ml of conc. ammonia. After stirring for 30 minutes the suspension obtained was evaporated and the residue was triturated with 30 ml of water. The white crystals were filtered off under suction and dried in a vacuum. There were obtained 2.8 g (92%) of (S)-7-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide of m.p. 251°-253°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]=[CH2:11])[CH:5]=[C:4]([F:12])[CH:3]=1.C([Li])CCC.[I:18]I>CCCCCC.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]=[CH2:11])[CH:5]=[C:4]([F:12])[C:3]=1[I:18]
Reactant: C=CCCc1cc(F)cc(F)c1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCCc1cc(F)c(I)c(F)c1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 104.5 %

Procedure:
0.41 mol 1,3 difluoro-5-(3-butenyl)-benzene was added to a dry round bottom flask with 300 ml anhydrous tetrahydrofuran. After cooling under a nitrogen atmosphere to −70° C. a solution of 0.46 mol of n-butyllithium in 280 ml hexane was added. After stirring at −70° C. for 30 minutes a mixture of 0.46 mol of Iodine in 200 ml tetrahydrofuran was added slowly over 2 hours. The reaction was left to warm to room temperature overnight. The reaction was quenched by pouring onto ice/hydrochloric acid mixture. The layers were separated and the aqueous layer extracted twice with diethyl ether (2×100 ml). The combined organic layers were washed with 50 g sodium thiosulphate in 200 ml water to remove excess iodine, then with water (2×50 ml) and dried over anhydrous sodium sulphate. Removal of the solvent yielded 126 g of the title compound as a beige solid.
Reaction SMILES: [N:1](=[C:3]1[CH2:8][S:7][CH2:6][CH2:5][S:4]1)[OH:2].[CH3:9][N:10]([S:14][C:15]([CH3:22])([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH3:16])[C:11](Cl)=[O:12].C(N(CC)CC)C>O1CCOCC1>[CH3:9][N:10]([S:14][C:15]([CH3:16])([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH3:22])[C:11]([O:2][N:1]=[C:3]1[CH2:8][S:7][CH2:6][CH2:5][S:4]1)=[O:12]
Reactant: ON=C1CSCCS1
Reactant: CC(C)C(=O)C(C)(C)SN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)C(=O)C(C)(C)SN(C)C(=O)ON=C1CSCCS1

Procedure:
Prepared as in Example 1 by reacting 8.0 g (0.053 m) of 2-oximino-1,4-dithiane, 15.2 g (0.058 m) of N-methyl-N-(2,4-dimethyl-3-oxo-2-pentanesulfenyl)carbamoyl chloride and 5.42 g (0.053 m) of triethylamine in 100 ml of dioxane. The product crystallized from isopropyl ether-ethyl acetate to yield 4.3 g of a white solid, (m.p. 80°-82° C.) Recrystallization raised the melting point to 85°-86° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]([F:17])([F:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1C=[N:22][C:21]2N(O)N=[N:26][C:20]=2[CH:19]=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[C:21]([C:20]1([NH:26][C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][C:14]([F:17])([F:16])[CH3:15])=[O:12])[CH2:19][CH2:18]1)#[N:22]
Reactant: On1nnc2cccnc21
Reactant: CC(F)(F)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(F)(F)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(C#N)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
1.35 g (5.33 mmol) of the product from example 16, 810 mg (6.83 mmol, 1.3 eq.) of 1-amino-1-cyclopropylnitrile hydrochloride and 943 mg (6.93 mmol, 1.3 eq.) of HOAt were dissolved or suspended in 18 ml of dichloromethane, cooled to 0° C. and then admixed with 1.33 g (6.93 mmol, 1.3 eq.) of EDCl and 1.76 ml (1.596 g, 13.86 mmol, 2.6 eq.) of NEM. The mixture was stirred at 0° C. to RT for 16 h. The reaction mixture was then diluted with 40 ml of DCM and extracted by shaking with 1 N HCl solution, saturated sodium hydrogencarbonate solution and saturated NaCl solution. The organic phase was dried over sodium sulfate and concentrated by evaporation under reduced pressure. The product was sufficiently clean for further reactions.
Reaction SMILES: [Na].[ClH:2].[NH2:3][OH:4].[Cl-].[Na+].[NH2:7][C:8]1[CH:22]=[CH:21][C:11]([C:12]([NH:14][CH2:15][C:16](OCC)=[O:17])=[O:13])=[CH:10][CH:9]=1>CO>[ClH:2].[NH2:7][C:8]1[CH:22]=[CH:21][C:11]([C:12]([NH:14][CH2:15][C:16]([NH:3][OH:4])=[O:17])=[O:13])=[CH:10][CH:9]=1
Reactant: NO
Reactant: CCOC(=O)CNC(=O)c1ccc(N)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(C(=O)NCC(=O)NO)cc1
Yield: 72 %

Procedure:
5.75 g (0.25 gram atom) of sodium are added in small pieces to 150 ml of anhydrous methanol, and this cold solution of sodium methylene is then poured into a solution of 10.5 g (0.15 mol) of hydroxylamine hydrochloride in 100 ml of anhydrous methanol. The mixture is stirred for half an hour in the cold, the sodium chloride precipitate is filtered off and 22.2 g (0.1 mol) of ethyl 4-aminobenzamidoacetate are added to the filtrate; after leaving the reactants in contact overnight, the mixture is evaporated to dryness in vacuo, the residue is taken up in 100 ml of water and the hydrochloride is precipitated by adding 6 N HCl up to pH=1, and is filtered off and washed with 10 ml of cold water. CRL 40,473 is thus obtained by recrystallisation from a 4:1 (volume/volume) mixture of methanol and water. Melting point 182°-185° C. (with decomposition). Yield: 72%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=1>CC(N(C)C)=O>[F:9][C:3]1[CH:4]=[C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A solution of 4-amino-3-fluorophenol (5.00 g, 39.3 mmol) in anhydrous DMA (100 mL) was treated with potassium tert-butoxide (5.30 g, 47.2 mmol), and the red-brown mixture was stirred at room temperature for 1 h. The mixture was treated with a solution of 4-chloro-2-picoline (5.02 g, 39.3 mmol) in anhydrous DMA (75 mL) and then heated at 100° C. for 17 h. The mixture was cooled to ambient temperature and partitioned between EtOAc (500 mL) and saturated NaCl solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated at reduced pressure. Purification through a silica gel plug, eluting with 40% EtOAc/hexane, followed by crystallization from DCM/hexane afforded 4.06 g (47%) of the title compound as a yellow solid. 1H-NMR (DMSO-d6) δ 8.24 (d, J=5.4 Hz, 1H), 6.91 (dd, J=12.3, 2.7 Hz, 1H), 6.80 (dd, J=9.6, 8.7 Hz, 1H), 6.72 to 6.62 (m, 3H), 5.15 (broad s, 2H), (2.36 (s, 3H); MS LC-MS [M+H]+=219, RT=0.24 min.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.B.O1CCCC1>CO>[N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: N#Cc1ccc(-n2cccn2)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc(-n2cccn2)cc1
Yield: 83 %

Procedure:
To 4-(pyrazol-1-yl)benzonitrile (see WO 2005/095343A) (1.46 g, 8.63 mmol) was added a solution of 1M borane.tetrahydrofuran complex in tetrahydrofuran (93 ml, 93 mmol), followed by heating to reflux for 16 hours. After completion of the reaction, methanol (14 ml) was added to the reaction solution, followed by concentration under reduced pressure. 6N Hydrochloric acid (265 ml) was added to the residue, followed by further heating to reflux for 3 hours. After this solution was concentrated under reduced pressure, a small amount of water was added. The resulting solution was adjusted to pH 11 with a 30% aqueous sodium hydroxide solution under ice cooling, followed by extraction with methylene chloride. The separated organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=90:10:1 (V/V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (1.24 g) as a pale yellow solid. (Yield: 83%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]=[C:24]=[O:25].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:22][NH:23][C:24](=[O:25])[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:9][CH2:10][C:11](=[O:21])[N:12]2[CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH:3]=1
Reactant: O=C1CCC(c2cccc(O)c2)N1CCN1CCOCC1
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCC(=O)N2CCN2CCOCC2)c1
Yield: 89 %

Procedure:
To a solution of 5-(3-hydroxyphenyl)-1-[2-(4-morpholinyl)ethyl]-2-pyrrolidinone (1.1 g) in dry tetrahydrofuran (50 ml) was added methyl isocyanate (0.26 ml) at ambient temperature, with stirring, over ten mins. Milled potassium carbonate was added, and the reaction mixture was stirred for 17 hrs. The mixture was filtered through a pad of celite. The filter cake was washed with ethyl acetate and the combined filtrates were concentrated. The residue was purified by flash column chromatography (silica gel, ether/0-50% methanol). The appropriate fractions were collected and concentrated to give 1.2 g (89%) of product. Crystallization of the residue from ether gave the analytical sample, mp 100°-102° C.
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:14][N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:10]([CH:13]=1)[CH2:11][NH2:12].[C:21]([N:28]1[CH2:35][CH2:34][CH2:33][C@H:29]1[C:30](O)=[O:31])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:14][N:15]2[CH2:16][C:17]([F:20])([F:19])[CH2:18]2)=[C:10]([CH:13]=1)[CH2:11][NH:12][C:30](=[O:31])[C@@H:29]1[CH2:33][CH2:34][CH2:35][N:28]1[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22]
Reactant: NCc1cc(Cl)ccc1CN1CC(F)(F)C1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CN1CC(F)(F)C1
Yield: 51.7 %

Procedure:
EDC (80.2 mg, 0.42 mmol) was added to a stirred mixture of 5-chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]benzylamine (68.8 mg, 0.28 mmol), N-BOC-L-proline (60.0 mg, 0.28 mmol) and HOAT (19.0 mg, 0.14 mmol) in DMF (2.5 mL). After 66 h the reaction mixture was concentrated and the residue was partitioned between EtOAc and 10% NaHCO3. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica (eluting with EtOAc/CHCl3, 1:5) to give N-{5-chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]benzyl}-1-(tert-butoxycarbonyl)-L-prolinamide (64.2 mg) as a glass: MS: 444.4 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[C:27]([O:28][C:29]2[C:38]3[C:33](=[CH:34][C:35](O)=[C:36]([O:39][CH3:40])[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[C:22]([CH3:42])[NH:23]2>>[F:18][C:19]1[C:27]([O:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([O:17][CH2:16][CH2:15][CH2:14][N:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]4)=[C:36]([O:39][CH3:40])[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[C:22]([CH3:42])[NH:23]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Yield: 70 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 11, 1-tert-butoxycarbonyl-4-(3-hydroxypropyl)piperazine (432 mg, 1.77 mmol) was reacted with 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline (500 mg, 1.47 mmol), (prepared as described for the starting material in Example 7). The product was purified by column chromatography, eluting with 2%-5% methanol/methylene chloride to give tert-butyl 4-[3-(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-yloxy)propyl]piperazine-1-carboxylate (582 mg, 70%).
Reaction SMILES: [C:1]([CH:6]=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O:3][CH2:4][CH3:5])=[O:2].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[C:38](Cl)(=[O:47])[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:46][O:45][C:42]1[CH:43]=[CH:44][C:39]([C:38](=[O:47])[C:6](=[P:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:40][CH:41]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)c1ccc(OC)cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (carbethoxymethylene)triphenylphosphorane (0.500 g, 1.44 mmol) in DCM (7 ml) under an N2 atmosphere was added N,O-bis(trimethylsilyl)acetamide (0.42 m, 1.7 mmol). The solution was then cooled to 0° C. and p-anisoylchloride (0.250 g, 1.47 mmol) was added. The reaction mixture was then gradually warmed to room temperature and stirred overnight. The reaction was quenched by the addition of H2O (3 ml) and the aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4 and the solvent removed in vacuo to afford ethyl 3-(4-methoxyphenyl)-3-oxo-2-(triphenylphosphoranylidene)propionate. (0.637 g, 1.32 mmol, 92%) as an off white solid which was used without further purification. 1H NMR (CDCl3) δ 0.62 (3H, t), 3.69 (2H, q), 3.82 (3H, s), 6.86 (2H, d), 7.43-7.55 (9H, m), 7.71-7.80 (8H, m). LCMS (2) Rt: 3.65 min; m/z 483.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[F:20]C1C=CC=C2C=1NC=C2>>[F:20][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2
Reactant: Fc1cccc2cc[nH]c12
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: CC1(C)OB(c2cc3cccc(F)c3[nH]2)OC1(C)C

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-fluoro-1H-indole.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](NC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:36]1([C@H:42]([NH2:44])[CH3:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:44][C@@H:42]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH3:43])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3C)c(=O)n(C)c2n1
Reactant: C[C@@H](N)c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(F)c(NC(=O)Nc2cnn(C(C)(C)C)c2)cc1-c1cc2cnc(N[C@H](C)c3ccccc3)nc2n(C)c1=O
Yield: 52.8 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 109 (0.081 g, 0.16 mmol) and (R)-1-phenylethanamine (0.058 g, 0.48 mmol) were combined in THF (1 mL) to provide (R)-1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-7-oxo-2-(1-phenylethylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as a white solid (0.048 g, 53% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.62 (s, 1H), 8.60 (s, 1H), 8.48 (d, J=7.2 Hz, 1H), 8.39 (brs, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.43-7.35 (m, 3H), 7.31-7.27 (m, 2H), 7.18 (t, J=7.2 Hz, 1H), 7.08 (d, J=12.8 Hz, 1H), 5.12 (t, J=7.2 Hz, 1H), 3.54-3.46 (m, 3H), 2.01 (s, 3H), 1.44 (s, 9H); (ESI) m/z: 569.3 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=4[N:18](C(C)=C)[C:17]3=[O:29])[CH2:9][CH2:8]2)[C:5]2[CH:30]=[CH:31][CH:32]=[CH:33][C:4]=2[NH:3]1.[ClH:34].O>C(O)C>[OH2:1].[ClH:34].[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=4[NH:18][C:17]3=[O:29])[CH2:9][CH2:8]2)[C:5]2[CH:30]=[CH:31][CH:32]=[CH:33][C:4]=2[NH:3]1
Reactant: C=C(C)n1c(=O)n(CCCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2ccc(C)cc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)[nH]c(=O)n2CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of 6 parts of 1-{3-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one, 12 parts of a hydrochloric acid solution, 30 parts of water and 40 parts of ethanol is stirred first for a while at 50° C. and further for 1 hour at room temperature. The reaction mixture is evaporated and the residue is crystallized from a mixture of 4-methyl-2-pentanone and 2-propanol. The product is filtered off and dried, yielding 3.7 parts (40%) of 1-{3-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-2H-benzimidazol-2-one hydrochloride hydrate; mp. 251.4° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:8][N:7]([CH3:9])[C:6](=O)[N:5]1[CH3:11].P(Cl)(Cl)(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].C([O-])(=O)/C=C/C([O-])=O>C(Cl)(Cl)Cl.C(O)(C)C>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:8][N:7]([CH3:9])[C:6](=[N:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]1[CH3:11]
Reactant: Nc1ccccc1
Reactant: CN1CC(CCCl)N(C)C1=O
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CN1CC(CCCl)N(C)C1=Nc1ccccc1
Reaction time: 2 h
Yield: 50 %

Procedure:
To 8.0 g (0.045 mole) of 4-(2-chloroethyl)-1,3-dimethyl-2-oxo-imidazolidine was added 50 ml of phosphorus oxychloride, and the solution was refluxed for 18 hours, and concentrated in vacuo. The residue was dissolved in 25 ml of methylene chloride and added dropwise to 4.2 g (0.045 mole) of aniline stirring at room temperature. Stirring was continued for two hours. The solution was diluted with chloroform and washed with dilute sodium hydroxide solution. The chloroform was dried, filtered and concentrated in vacuo. The residue was dissolved in isopropyl alcohol and treated with 5.2 g. (0.045 mole) fumaric acid, and the resulting fumarate was recrystallized from isopropyl alcohol and weighed 9.0 g (50% yield); m.p. 109°-112° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.I[C:15]1[O:19][C:18]([CH3:20])=[N:17][C:16]=1[CH3:21].C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:20][C:18]1[O:19][C:15]([C:6]2[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)=[C:16]([CH3:21])[N:17]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Cc1nc(C)c(I)o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: COc1ncc(-c2oc(C)nc2C)c(OC)n1
Yield: 67.1 %

Procedure:
2,4-Dimethoxy-pyrimidine-5-boronic acid (840 mg, 4.6 mmol) was dissolved in degassed n-PrOH (40 mL) and then 5-iodo-2,4-dimethyl-oxazole (Prep60, 850 mg, 3.8 mmol), Na2CO3 (848 mg, 8 mmol), PPh3 (332 mg, 1.3 mmol) and Pd(OAc)2 (85 mg, 0.38 mmol) were added. The suspension was stirred at reflux for 4 hours. The solvent was evaporated under vacuum and the crude was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by SCX cartridge to give 600 mg of the title compound (66% yield).