Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[NH:9][CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])#[N:4].[NH2:24]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1.[Na]>CN(C=O)C.C(OCC)(=O)C>[NH2:24][N:9]1[C:5]([C:3]#[N:4])=[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8]1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1c[nH]c(C#N)c1-c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c(C#N)c1-c1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 3.02 g, 75.6 mmol) was added to a solution ethyl 5-cyano-4-(nitrophenyl)-1H-pyrrole-3-carboxylate (17.97 g, 63.00 mmol) in DMF (625 mL). The solution was stirred at it for 15 min and then (aminooxy)(diphenyl)phosphine oxide (17.63 g, 75.59 mmol) was added, and the solution was heated (80° C.) for 17 h. Upon cooling to it aqueous saturated sodium bircarbonate solution (500 mL) was added followed by ethyl acetate (400 mL). The layers were separated and the aqueous layer was back extracted with ethyl acetate (2×200 mL). The combined organic layers dried over sodium sulfate and concentrated to dryness. The crude material was triturated with dichloromethane-hexanes (1:1 v/v 400 mL). The solid was collected, washed with hexanes (100 mL), and dried under vacuum. The material was suspended in ethyl acetate (500 mL) and, heated to reflux for 15 min, and then filtered. The filtrate was concentrated in vacuo to afford the desired product (14.15 g, 75%). 1H-NMR (300 MHz, DMSO-d6) 8.25-8.31 (m, 2H), 7.73 (s, 1H), 7.67-7.73 (m, 2H), 6.71 (br s, 2H), 4.12 (q, J=7.1 Hz, 2H), 1.16 (t, J=7.1 Hz, 3H); HPLC RT (Method A) 2.91 min; TLC Rf=0.30 (95:5 v/v CH2Cl2-EtOAc).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].[CH2:15]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH3:18]>CN(C)C=O>[CH2:15]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH3:18]
Reactant: Nc1ncccc1-c1cn[nH]c1
Reactant: CCCCOCc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOCc1ccc(Cn2cc(-c3cccnc3N)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To a mixture of 3-(1H-pyrazol-4-yl)-pyridin-2-ylamine (20 mg, 0.13 mmol) described in Manufacturing Example 32-1-4 and N,N-dimethylformamide (1 mL) was added sodium hydride (6.8 mg, 0.19 mmol, 66% in oil), which was stirred for 30 minutes at room temperature. 1-Butoxymethyl-4-chloromethyl-benzene (29 mg, 0.14 mmol) described in Manufacturing Example 33-1-4 was added to the reaction mixture at room temperature, and stirred for 1.5 hours at 40° C. The reaction mixture was cooled and partitioned into water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (33 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:15]([O:17]CC)=[O:16])[N:12]([CH3:14])[N:13]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[N:12]([CH3:14])[N:13]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2Cl)nn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(-c2ccc(Cl)cc2Cl)cc1C(=O)O
Temperature: 25 °C
Yield: 70.4 %

Procedure:
Ethyl 5-(2,4-dichlorophenyl)-2-methyl-2H-pyrazole-3-carboxylate (2.98 g) was added to ethanol (50 ml), and sodium hydroxide (5.0 g) was added thereto at a room temperature under stirring, and subsequently the mixture was heated and stirred for 60 minutes. The mixture was adjusted to pH 5 by addition of 2-N hydrochloric acid, and the precipitated crystal was separated by filtration and subjected to through circulation drying to give the title compound (1.90 g, 70%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:56]1([N:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH2:58][CH2:57]1>CN(C=O)C>[CH:56]1([N:59]2[CH2:64][CH2:63][N:62]([C:31](=[O:32])[CH2:30][C:26]3[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]4\[C:17](=[O:22])[NH:18][C:19]5[C:15]\4=[CH:14][C:13]([S:10]([CH2:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=5)[NH:28][C:27]=3[CH3:29])[CH2:61][CH2:60]2)[CH2:58][CH2:57]1
Reactant: C1CN(C2CC2)CCN1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CCN(C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (208 mg, 0.4 mmol), HOBt (54 mg, 1 eq.) and EDAC (153 mg, 2 eq.) in DMF (1.5 mL) was stirred at rt for 30 mins. To the mixture was added 1-cyclopropyl-piperazine (101 mg, 2 eq.) in DMF (1.5 mL). After stirring at rt for overnight, the precipitate was collected by vacuum filtration, washed with water, sodium bicarbonate and ether to give 108 mg (43%) of the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11]Cl)[N:10]=[C:4]2[CH:3]=1.[CH3:13][O-:14].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11][O:14][CH3:13])[N:10]=[C:4]2[CH:3]=1
Reactant: C[O-]
Reactant: ClCc1cn2ccc(Br)cc2n1
Agent: [Na+]
Solvent: CO
Product: COCc1cn2ccc(Br)cc2n1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
To a solution of 81 mg (0.33 mmol) of 7-bromo-2-chloromethylimidazo[1,2-a]pyridine, prepared according to the protocol described in step 8.3, in 3 mL of anhydrous methanol, stirred at room temperature under an inert atmosphere, are added 35 mg (0.99 mmol) of sodium methoxide. The reaction mixture is stirred at 100° C. for 4 hours. After this time, the reaction medium, cooled to room temperature, is concentrated under reduced pressure, diluted with 10 mL of chloroform and then washed with 10 mL of saturated aqueous NaCl solution. The crude reaction product obtained after evaporating off the solvent under reduced pressure is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 27 mg of the expected product are thus obtained.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([F:19])=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[F:12])(=O)C.[OH-].[Na+].CO>C(O)(=O)C>[F:19][C:7]1[C:6]([CH2:5][OH:4])=[C:11]([F:12])[CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)OCc1c(F)ccc(-c2ccccc2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: OCc1c(F)ccc(-c2ccccc2)c1F
Yield: 87 %

Procedure:
A solution of 3.1 g (0.012 mole) of (2,4-difluoro[1,1'-biphenyl]-3-yl)methyl acetate in 25 ml of a 2% aqueous solution of sodium hydroxide and 75 ml of methanol was stirred at ambient temperature until the reaction was complete as indicated by thin layer chromatography. The reaction mixture was neutralized with glacial acetic acid and concentrated under reduced pressure to give a residual solid. The solid was partitioned between diethyl ether and water. The phases were separated and the aqueous phase was extracted with two portions of diethyl ether. The ether layers were combined and washed with one portion of 150 ml of 2% aqueous hydrochloric acid, one portion of 150 ml of water, one portion of 150 ml of a 10% aqueous solution of sodium carbonate, one portion of 150 ml of water, and finally, one portion of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 2.3 g of 2,4-difluoro[1,1'-biphenyl]-3-methanol. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[Si:29]([CH3:32])([CH3:31])[CH3:30]>O1CCCC1.CCCCCC>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=[C:24]([O:26][CH3:27])[O:25][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)Cc1ccccc1OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=Cc1ccccc1OCc1ccccc1)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a dry ice-acetone bath cooled 1.45M solution of lithium diisopropylamide in a mixture of tetrahydrofuran and n-hexane (1.4 ml) was added methyl (2-benzyloxyphenyl)acetate (256 mg). The mixture was stirred for 30 minutes at the same temperature and then for 30 minutes at 0° C. After cooling the solution to −78° C. chlorotrimethylsilane (0.3 ml) was added and the mixture was allowed to warm to room temperature. The solution was diluted with n-hexane (50 ml), filtered through celite, and concentrated under reduced pressure to afford 2-(2-benzyloxyphenyl)-1-methoxy-1-trimethylsilyloxyethylene. To an ice bath cooled solution of (2S)-3-methyl-2-(p-tolylsulfonylamino)butanol (288 mg) in dichloromethane (10 ml) was added a 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran (1.0 ml) and the mixture was stirred for 30 minutes at ambient temperature. After cooling the solution to −78° C., cyclohexanecarbaldehyde (112 mg) and a solution of 2-(2-benzyloxyphenyl)-1-methoxy-1-trimethylsilyloxyethylene prepared above in dichloromethane (1 ml) were added. The solution was stirred for one hour at −78° C. and then quenched by an aqueous solution of sodium bicarbonate at 0° C. The mixture was extracted with diethyl ether, dried and evaporated in vacuo. The residue was dissolved in a mixture of tetrahydrofuran (4 ml) and aqueous 1M solution of hydrochloric acid (2 ml), and the resulting solution was allowed to stand for 30 minutes. Aqueous solution of sodium bicarbonate was added thereto and the mixture was extracted with ether. The organic layer was dried and evaporated. Preparative thin layer chromatography [silica gel, ether - hexane (1:4)] afforded methyl (2R,3R)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionate (187 mg). High pressure liquid chromatography analysis (Daicel AD column eluting with 20% isopropyl alcohol - hexane) indicated an enantiomeric excess of 95% (Rt: major 10.51 minutes, minor 8.60 minutes).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH2:11]Cl)=[CH:4][CH:3]=1.[C-:17]#[N:18].[Na+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH2:11][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: Fc1ccc(Sc2ccccc2CCl)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccccc1Sc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 26 h

Procedure:
12.0 g of 2-(4-fluorophenylthio)benzyl chloride are added portionwise over a 30 minute span to a mixture of 2.9 g of sodium cyanide in 120 ml of dimethylsulfoxide. After total addition, the reaction mixture is stirred for 26 hours before being poured onto 150-200 ml of crushed ice. The mixture is extracted four times with 70 ml portions of ether and the combined ether extracts are successively washed four times with 50 ml portions of water, washed once with 25 ml of saturated sodium chloride solution and dried, providing 2-(4-fluorophenylthio)benzyl cyanide.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[C:30]([N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:24][CH3:25])[N:10]=[CH:9][N:8]=[C:7]2[NH:6][C:5]1[CH:26]=[CH:27][CH:28]=[C:3]([Cl:2])[C:4]=1[F:29])(=[O:32])[CH3:31]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(C)=O
Yield: 92 %

Procedure:
Using a similar procedure to that described in Example 38, 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride (300 mg; prepared as described in Example 31) was reacted with acetic anhydride to give the title product (280 mg, 92%); 1H NMR Spectrum: (DMSO d6) 1.89-2.05 (m, 6H); 2.15 (m, 1H); 3.43-3.56 (m, 2H); 3.93 (s, 3H); 4.00-4.11 (m, 1H); 4.17-4.21 (m, 1H); 4.32-4.42 (m, 1H); 7.19-7.29 (m, 2H); 7.41-7.54 (m, 2H); 7.79-7.82 (m, 1H); 8.36-8.37 (m, 1H); 9.52-9.55 (m, 1H); Mass Spectrum: (M+H)+ 445.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH:16]1[CH2:18][CH2:17]1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](Cl)=[O:25]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][CH:16]1[CH2:17][CH2:18]1)[C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:21]([C:20]([F:19])([F:34])[F:35])[CH:22]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ccccc1-c1ccncc1NCC1CC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(CC1CC1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-cyclopropylmethyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 40:60) for the chromatographic purification. Light yellow oil (27%). MS (ESI): m/z=499.1005 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2c[nH]c3ccccc23)cc1
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc(-c2cn(-c3ccncc3)c3ccccc23)cc1
Reaction time: 18 h

Procedure:
3-(4-Fluorophenyl)-1H-indole 1a (39.3 g), 4-chloropyridine hydrochloride (55.8 g), K2CO3 (102.8 g), CuBr (15 g) and N-methylpyrrolidinone (1.2 l) were refluxed under stirring for 18 h. The reaction mixture was cooled, poured into water (1.0 l) and extracted with diethyl ether (2×1 l). The combined organic phases were washed with brine (3×1.5 l), dried (Na2SO4) and treated with activated carbon. Evaporation of the solvent gave the title compound which was crystallized from diethyl ether. Yield: 42.0 g, mp 115°-118° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([F:25])[C:20]=1[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:33]1[N:38]=[CH:37][C:36]([CH2:39][O:40][CH3:41])=[CH:35][N:34]=1>CS(C)=O.CCOC(C)=O>[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([F:25])[C:20]=1[S:21]([CH3:24])(=[O:22])=[O:23])[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:13][CH2:14][N:15]([C:33]2[N:38]=[CH:37][C:36]([CH2:39][O:40][CH3:41])=[CH:35][N:34]=2)[CH2:16][CH2:17]1
Reactant: CS(=O)(=O)c1c(F)cc(COC[C@@H]2C[C@@H]2C2CCNCC2)cc1F
Reactant: COCc1cnc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3COCc3cc(F)c(S(C)(=O)=O)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.9 %

Procedure:
4-((1R,2R)-2-(((3,5-difluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidine hydrochloride (Step C product, 100 mg, 0.25 mmol) was dissolved in DMSO (3 ml) at RT under N2 and Cs2CO3 (288 mg, 0.884 mmol) was added. The mixture was stirred at RT for 5 min and 2-chloro-5-methoxymethylpyrimidine (Intermediate 18, 48 mg, 0.3 mmol) in DMSO (0.5 mL) was added. The mixture was stirred at 60° C. overnight. The mixture was diluted with EtOAc, washed with sat. NH4Cl, dried over MgSO4, and evaporated to dryness. The crude material was purified by preparative TLC (60% EtOAc in hexane) to afford 50.5 mg (41.5%) of the desired product. LC/MS (m/z): 482 (M+H)±1H NMR (500 MHz, CDCl3) δ 8.30 (s, 2H), 7.15 (dd, 2H), 4.80-4.64 (m, 4H), 4.25 (s, 2H), 3.60 (m, 2H), 3.37 (s, 3H), 3.35 (s, 3H), 2.93-2.80 (m, 2H), 1.96-1.80 (m, 2H), 1.40-1.10 (m, 4H), 0.94-0.71 (m, 2H), 0.12-0.08 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH:4]=O)=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[C:9]([NH2:14])[C:8]=1[NH2:15]>CCO>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[C:9]2[C:8]=1[N:15]=[CH:1][C:2]([CH3:4])=[N:14]2
Reactant: CC(=O)C=O
Reactant: Nc1c(Br)ccc(Br)c1N
Solvent: CCO
Product: Cc1cnc2c(Br)ccc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
A 40% aqueous solution of methylglyoxal (6.7 M, 6.3 mL, 112 mmol, 1.48 equiv) was added to a suspension of 3,6-dibromo-benzene-1,2-diamine (Step 1.6) (20 g, 75.5 mmol) in EtOH (400 mL). The reaction mixture was stirred for 2 h at rt and for 0.5 h at reflux, allowed to cool and filtered to afford 7.66 g of the title compound. The filtrate was concentrated and the residue triturated in EtOAc and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (Hex/EtOAc, 1:0→9:1) to provide additional 2.15 g of the title compound. The title compound: ESI-MS: 300.9/302.9/304.9 [M+H]+; tR=4.81 min (System 1); TLC: Rf=0.90 (Hex/EtOAc, 1:1).
Reaction SMILES: Cl.Cl[CH:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[F:25])[CH3:4].[CH3:26][NH:27][C@@H:28]([C:30]([NH2:32])=[O:31])[CH3:29]>>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([NH:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([CH:3]([N:27]([CH3:26])[C@@H:28]([C:30]([NH2:32])=[O:31])[CH3:29])[CH3:4])[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CN[C@H](C)C(N)=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C(C)Cl
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C(C)N(C)[C@H](C)C(N)=O

Procedure:
6-(1-Chloroethyl)-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine hydrochloride (described in Example 91) was coupled with N2-methyl-D-alaninamide using an analogous method to that described for the equivalent step in Example 62 to give N2-(1-{4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}ethyl)-N2-methyl-D-alaninamide as a 1:1 mixture of diastereoisomers; 1H NMR Spectrum: (DMSO d6) 1.03 and 1.08 (both d, 1.5H); 1.38 (d, 3H); 2.06 and 2.22 (both s, 1.5H); 3.13 and 3.51 (both q, 0.5H); 3.97 (s, 3H); 4.31 (m, 1H); 7.07 (s, 1H); 7.22 (m, 1H); 7.23 (m, 1.5H); 7.44 (s, 0.5H); 7.53 (m, 2H); 8.44 (m, 1.5H); 8.60 (s, 0.5H); 9.77 and 9.80 (both s, 0.5H). Mass Spectrum: (M+H)+ 432.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[NH:30]([CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: Nc1ccccc1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC1(CNc2ccccc2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: -10 °C
Yield: 56.9 %

Procedure:
2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.10 g) dissolved in methylene chloride (15 ml). To this solution was added aniline (0.28 g) under cooling at -10° C. and then silver fluoroborate (0.43 g), after which the mixture was stirred for 2 hours. After the reaction was completed, the reaction mixture was washed with a dilute phosphoric acid aqueous solution and then with water, dried over magnesium sulfate, after which the solvent was distilled off. The residue was subjected to column chromatography on silica gel (20 g) and eluted with chloroform. The eluate was separated into fractions of each about 20 ml. The second to seventh fractions were collected and the solvent was distilled off to give 2,2,2-trichloroethyl 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.64 g), mp 148° to 149° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](Cl)=[N:7][OH:8])#[N:2].[C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)#[CH:14].N>>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:13]2[O:8][N:7]=[C:6]([C:5]3[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=3)[C:1]#[N:2])[CH:14]=2)[CH:16]=1
Reactant: C#Cc1cccnc1
Reactant: N#Cc1cccc(C(Cl)=NO)c1
Agent: N
Product: N#Cc1cccc(-c2cc(-c3cccnc3)on2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 18B (91 mg, 0.5 mmol) and 3-ethynylpyridine (Aldrich, 52 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.64 (dd, J=7.5, 4.4 Hz, 1H), 7.80 (t, J=7.5 Hz, 1H), 7.89 (s, 1H), 8.04 (dt, J=7.7, 1.3 Hz, 1H), 8.21-8.34 (m, 2H), 8.38 (t, J=1.4 Hz, 1H), 8.74 (dd, J=4.8, 1.6 Hz, 1H), 9.13 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 248 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([CH2:6][C:7]2[N:15]3[C:10]([C:11]([NH2:16])=[N:12][CH:13]=[N:14]3)=[C:9]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([CH:25]=3)=[N:23][N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=4)[CH:8]=2)[CH2:3]1.Br[CH2:34][CH2:35][O:36][Si](C(C)(C)C)(C)C.C(N(CC)C(C)C)(C)C>C1COCC1>[NH2:16][C:11]1[C:10]2=[C:9]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([CH:25]=3)=[N:23][N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=4)[CH:8]=[C:7]([CH2:6][CH:4]3[CH2:5][N:2]([CH2:34][CH2:35][OH:36])[CH2:3]3)[N:15]2[N:14]=[CH:13][N:12]=1
Reactant: Nc1ncnn2c(CC3CNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1ncnn2c(CC3CN(CCO)C3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 60 °C
Reaction time: 16 h
Yield: 6 %

Procedure:
To a solution of 7-(azetidin-3-ylmethyl)-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine hydrochloride (100 mg, 0.22 mmol) in THF (1.5 mL) was added (2-bromoethoxy)-tert-butyldimethylsilane (53 μL, 0.25 mmol) and N,N-diisopropylethylamine (117 μl, 0.67 mmol). The reaction was heated (60° C.) for 17 h and then cooled to rt. The crude mixture was purified by preparative HPLC using a gradient elution from 20% to 50% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated. A solution of the residue in 1% HCl in 95:5 EtOH/H2O (4 mL) was stirred at rt for 16 h. The mixture was basified (pH 9) with the addition of saturated, aqueous NaHCO3 solution and was evaporated to remove volatiles. The remaining aqueous mixture was extracted with ethyl acetate (3×15 mL) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was triturated with Et2O to afford 6 mg (6%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1 H), 8.17 (s, 1 H), 7.83 (d, 1 H), 7.67 (s, 1 H), 7.26-7.39 (m, 5 H), 7.14 (d, 1 H), 6.77 (d, 1 H), 5.66 (s, 2 H), 4.11-4.27 (m, 2 H), 3.89-4.02 (m, 3 H), 3.53-3.63 (m, 2 H), 3.33-3.42 (m, 1 H), 3.10-3.30 (m, 4 H); ES-MS m/z 454.46 [M+H]+, HPLC RT (min) 1.96.