Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[F:3][C:4]([F:18])([CH2:14][CH2:15][CH2:16][OH:17])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:19]C(C)([O-])C.[K+]>O1CCCC1>[F:3][C:4]([F:18])([CH2:14][CH2:15][CH2:16][O:17][CH3:19])[CH2:5][O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCCCC(F)(F)COCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COCCCC(F)(F)COCc1ccccc1
Reaction time: 8 h

Procedure:
Excess methyl iodide (17 g, 120 mmoles) is added to the alcoholate previously prepared from 2,2-difluoro-1-benzyloxy-5-hydroxypentane (9.8 g, 42.6 mmoles) and potassium t-butoxide (5.6 g, 50 mmoles) in dry tetrahydrofuran (50 ml). The reaction mixture is kept at room temperature overnight, concentrated under vacuum, and the residue is deluted with water and ether. Usual extraction gives the title compound which is purified by chromatography on silica (ethyl acetate/petroleum ether: 20/80, RF: 0.9; 7.4 g, 71%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13]S(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][C:25](O)=[CH:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[C:19]([NH2:18])=[N:20][CH:21]=[CH:22]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Reactant: Nc1nccc2cc(O)ccc12
Product: Nc1nccc2cc(O[C@@H]3CCN(Cc4ccccc4)C3)ccc12

Procedure:
This compound was prepared from (S)-methanesulfonic acid 1-benzylpyrrolidin-3-yl ester and 1-amino-6-hydroxyisoquinoline by the procedure described in Example 1 to give the (R) 6-(1-benzylpyrrolidin-3-yloxy)-isoquinolin-1-ylamine product, El-MS: m/z=320.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH:4][C:5]([N:7](N=O)[CH2:8][CH2:9][Cl:10])=[O:6])[CH2:2][Cl:3].CCCCCC>C1C=CC=CC=1>[Cl:3][CH2:2][CH2:1][NH:4][C:5]([NH:7][CH2:8][CH2:9][Cl:10])=[O:6]
Reactant: O=NN(CCCl)C(=O)NCCCl
Solvent: c1ccccc1
Solvent: CCCCCC
Product: O=C(NCCCl)NCCCl

Procedure:
A suspension of 1.11 mmole (0.205 g) of 1,3-bis(2-chloroethyl)urea in 8 ml methylene dichloride at -10° C. was saturated with dinitrogen trioxide in 20% excess of theoretical. The heterogeneous mixture gradually changed to a green homogeneous solution. The methylene dichloride was evaporated, and the residue was extracted with 3× 10 ml hexane. Evaporation of the hexane gave 0.1773 g of oil which was the crude BCNU (NSC 409962). The hexane insoluble portion, 0.0649 g, when treated with benzene, gave 0.020 g of 1,3-bis(2-chloroethyl)urea which was benzene insoluble. The benzene solubles were processed through a silica column (1× 10 cm) and 0.0245 g of crude BCNU was obtained. The combined fractions of crude product amounted to 0.2018 g (85.1%).
Reaction SMILES: Br[CH2:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1.[CH2:18]([NH2:21])[CH:19]=[CH2:20].COC(C)(C)C.[ClH:28]>CO.C(OCC)C.C(OCC)(=O)C>[ClH:28].[CH2:18]([NH:21][CH2:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1)[CH:19]=[CH2:20].[CH2:18]([NH:21][CH2:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1)[CH:19]=[CH2:20]
Reactant: BrCC1=Cc2ccccc2Oc2ccccc21
Reactant: C=CCN
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CO
Solvent: CCOCC
Product: C=CCNCC1=Cc2ccccc2Oc2ccccc21
Reaction time: 0.5 h
Yield: 39 %

Procedure:
At 50° C. a solution of 0.5 ml (1.74 mmol) of 10-bromomethyl-dibenz[b,F]oxepine is squirted into a solution of 0.3 ml (4 mmol) of allylamine in 0.9 ml of anhydrous methanol and the mixture is stirred for 30 minutes. Tert-butyl methyl ether and ethyl acetate are added and the mixture is extracted 3× with 20 ml of 1N hydrochloric acid each time, the combined aqueous phases are rendered basic with potassium hydroxide pellets and extracted 2× with ethyl acetate, and the organic phases are dried over sodium sulfate and concentrated. 0.35 ml (0.7 mmol) of 2N ethereal hydrochloric acid is added to the crude amine (180 mg) in 2 ml of diethyl ether, and the precipitated white hydrochloride is washed with diethyl ether and dried under a high vacuum at 40° C. 200 mg (667 μmol)=39% of the title compound alias 10-allylaminomethyl-dibenz[b,f]oxepine are obtained in the form of white crystals; melting point: 148°-158° C.; 1H-NMr (CD3OD, 200 MHz). 3.74 (d, 2H); 4.35 (d, 2H), 5.55 (m, 2H); 5.95 (m, 1H); 7.20-7.58 (m, 9H); MS: 263 (M+, free base), 222, 208, 181, 165, 152.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH2:22]O)[CH:19]=[CH:20][CH:21]=1>>[Br:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Br)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2cccc(Br)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-bromophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.22 (2H, s), 5.74 (1H, s), 7.28 (1H, d, J=7.6 Hz), 7.35 (1H, d, J=7.6 Hz), 7.42 (1H, d, J=4.4 Hz), 7.49 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=1.2 Hz), 7.64 (1H, s), 8.05 (1H, s), 8.72 (1H, d, J=4.8 Hz). [M+H] Calc'd for C16H11BrN4O, 355; Found, 355.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C(NC(C)C)(C)C.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:14][Si:15]([CH3:17])([CH3:16])[C:18]#[C:19][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: Ic1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)C#Cc1cccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69747.9 %

Procedure:
A mixture of 2-iodothiophene (500 mg, 2.38 mmol), Pd(PPh3)2Cl2 (52.95 mg, 0.0754 mmol), CuI (28.1 mg, 0.14756 mmol) and diisopropylamine (0.62 ml, 4.4744 mmol) in THF (4 ml) was degassed thoroughly with argon, and trimethylsilyl acetylene (0.453 ml, 3.284 mmol) was added at room temperature. After stirring the reaction mixture for 16 hours at room temperature, it was poured into water and extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude material was purified by column chromatography (100-200 mesh silica gel) using hexane as eluent to yield 300 mg of trimethyl(thiophen-2-ylethynyl)silane (300 mg, 1.66 mol, yield 70.02%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:16][C:17]([CH2:19]Cl)=[CH2:18].[CH3:21][C:22]([C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Cl:14][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:12])[Cl:13])[CH:7]=[C:2]([Cl:1])[C:3]=1[O:15][CH2:16][C:17](=[CH2:18])[CH2:19][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:22](=[O:23])[CH3:21])=[CH:25][CH:26]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: C=C(CCl)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C=C(COc1ccc(C(C)=O)cc1)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 80 °C
Reaction time: 3 h

Procedure:
1.6 g of 1,3-dichloro-2-(2-chloromethyl-allyloxy)-5-(3,3-dichloro-allyloxy)-benzene and 686 mg of 4-hydroxyacetophenone are introduced into 25 ml of acetonitrile. 1.7 g of potassium carbonate and 50 mg of potassium iodide are then added and the mixture is stirred for 3 hours at 80° C. The reaction mixture is filtered and the filtrate is concentrated. After purification over silica gel, 1-(4-{2-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxymethyl]-allyloxy}-phenyl)-ethanone is obtained.
Reaction SMILES: C(#N)C.CC(O[CH2:8][C:9]1[CH2:18][S:17][C@@H:12]2[C@H:13]([NH2:16])[C:14](=[O:15])[N:11]2[C:10]=1[C:19]([OH:21])=[O:20])=O.[SH:22][C:23]1[O:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([OH:35])[CH:29]=2)=[N:26][N:27]=1.B(F)(F)F.CCOCC.N>O>[NH2:16][C@@H:13]1[C:14](=[O:15])[N:11]2[C:10]([C:19]([OH:21])=[O:20])=[C:9]([CH2:8][S:22][C:23]3[O:24][C:25]([C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([OH:35])[CH:29]=4)=[N:26][N:27]=3)[CH2:18][S:17][C@H:12]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Oc1ccc(-c2nnc(S)o2)cc1O
Agent: FB(F)F
Agent: N
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnc(-c4ccc(O)c(O)c4)o3)CS[C@H]12
Temperature: 50 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
To 520 ml of acetonitrile 16.3 g (60 mmol) of 7β-aminocephalosporanic acid and 13.9 g (66 mmol) of 2-mercapto-5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazole and 45.4 ml (360 mmol) of boron trifluoride diethyl etherate were added, and stirred at 50° C. for 3 hours. The reaction solution was cooled and poured into 450 ml of cold water. The mixture was stirred at room temperature for 1 hour and adjusted to pH2.0 with a 25% aqueous ammonia. The mixture was stirred at not more than 5° C. for 1 hour, and the precipitates were collected by filtration. The precipitates were washed with water and ethyl acetate and dried to obtain 21.3 g (yield: 84.1%) of the above identified compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([NH:11]C(=O)C2C=CC=CC=2)=[S:10])[N:3]=1.[OH-].[Na+].Cl.C(=O)(O)[O-].[K+]>>[Br:1][C:2]1[N:3]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(=S)Nc1cccc(Br)n1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Product: NC(=S)Nc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
A suspension of 2-bromo-6-benzoylthioureidopyridine (4.99 g, 14.84 mmol) in 10% aqueous sodium hydroxide solution (10.4 mL, 26 mmol) was stirred at rt. for 10 min and then under reflux for an additional 10 min. The mixture was cooled to 0° C. and acidified with 1 N aqueous HCl solution to pH 4.0 and then adjusted to pH 8.5 with satd. aqueous potassium bicarbonate solution. The mixture was stirred at 0° C. for several min and the precipitate was filtered, washed several times with water and dried in vacuo over P2O5 to obtain the titled compound (3.23 g, 94%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:15]([O-:17])=[O:16])=[C:7]([NH:11]C(=O)C)[CH:8]=2)[CH2:3]1>CCO.[CH]Cl>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:15]([O-:17])=[O:16])=[C:7]([NH2:11])[CH:8]=2)[CH2:3]1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CC(C)C2
Agent: [CH]Cl
Solvent: CCO
Product: CC1Cc2cc(N)c([N+](=O)[O-])cc2C1
Yield: 96.7 %

Procedure:
A suspension of nitroacetamide 92 (3.79 g, 16.2 mmol) in EtOH (100 mL) and cHCl (14 mL) was stirred at reflux temperature for 4 h. The mixture was cooled and the EtOH evaporated. The mixture was diluted with water (100 mL) and the pH adjusted to 9 with cNH3. The mixture was extracted with DCM (3×50 mL) and the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with 20% EtOAc/pet. ether, to give nitroaniline 93 (3.01 g, 97%) as a red solid: mp (EtOAc/pet. ether) 100-101° C.; 1H NMR δ 7.89 (s, 1H, H-7), 6.61 (s, 1H, H-4), 5.99 (br s, 2H, NH2), 2.92-2.99 (m, 2H, CH2), 2.40-2.58 (m, 3H, H-2, CH2), 1.12 (d, J=6.5 Hz, 3H, CH3); 13C NMR δ 153.9, 144.3, 133.6, 131.3, 120.9, 113.6, 41.1, 39.6, 34.8, 20.4. Anal. calcd for C10H12N2O2: C, 62.5; H, 6.3; N, 14.6. Found: C, 62.6; H, 6.3; N, 14.5%.
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:14])(=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11].[F:15][CH:16]([CH2:18][C:19](Cl)=[S:20])[F:17]>O1CCCC1>[C:8]([O:14][C:19](=[S:20])[CH2:18][CH:16]([F:17])[F:15])(=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)CC(=O)O
Reactant: FC(F)CC(=S)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CC(=O)OC(=S)CC(F)F
Reaction time: 1 h

Procedure:
To a stirred solution of triethylamine (1.4 equivalents) and isovaleric acid (1.3 equivalents) in tetrahydrofuran (5 parts by weight) is dropwise added difluoromethylthioacetyl chloride at -30° C., and the mixture is left standing for 1 hour. After removing separated crystals by filtration, the reaction mixture is concentrated in vacuum to leave difluoromethylthioacetic isovaleric anhydride.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:22][O:23][CH3:24].CCOC(C)=O>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH2:22][O:23][CH3:24])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCl
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)(C)C)nn1COC

Procedure:
Method I was used with ethyl 3-tert-butyl-1H-pyrazole-5-carboxylate (1078 mg, 5.49 mmol), caesium carbonate (2.89 g, 8.87 mmol) and chloro(methoxy)methane (426 μl, 5.60 mmol). 16 hours reaction time. Column eluent: 0→10% EtOAc in CH2Cl2. Yield: 485 mg (37%) of a colorless oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[N:17]2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.NN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:53][CH2:54][C:55]([N:57]1[CH2:62][CH2:61][CH:60]([O:63][C:64]2[CH:69]=[C:68]([F:70])[CH:67]=[CH:66][C:65]=2[Cl:71])[CH2:59][CH2:58]1)=[O:56]>CN(C=O)C.O>[Cl:71][C:65]1[CH:66]=[CH:67][C:68]([F:70])=[CH:69][C:64]=1[O:63][CH:60]1[CH2:61][CH2:62][N:57]([C:55](=[O:56])[CH2:54][NH:53][C:21]([C:19]2[N:18]=[N:17][N:16]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[CH:20]=2)=[O:23])[CH2:58][CH2:59]1
Reactant: NCC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1
Reactant: O=C(O)c1cn(N2CCOCC2)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1)c1cn(N2CCOCC2)nn1
Reaction time: 0.03 h
Yield: 70.3 %

Procedure:
DIPEA (200 mg, 1.54 mmol) was added to a stirred solution of 1-morpholin-4-yl-1H-[1,2,3]triazole-4-carboxylic acid (prepared by the method used for the synthesis of Intermediate 64, starting from 4-aminomorpholine) (70 mg, 0.35 mmol) in DMF (5 mL) followed by HOBt (52 mg, 0.38 mmol) and EDCI (170 mg, 0.88 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (125 mg, 0.38 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the precipitate was collected. The solid was purified by recrystallizing from a mixture of 20% ethyl acetate in hexane and MeOH to afford 116 mg (70.3% Yield) of 1-morpholin-4-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 467.15, 96.7%. 1H NMR (300 MHz, DMSO-d6): δ 8.8 (s, 1H), 8.4 (t, 1H), 7.5 (t, 1H), 7.3 (d, 1H), 6.8 (t, 1H), 4.9 (m, 1H), 4.2 (d, 2H), 3.85 (t, 4H), 3.7 (d, 2H), 3.5 (b, 2H), 3.3 (bs, 4H), 2.0 (d, 2H), 1.8 (d, 2H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[CH3:32][O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]>>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([C:2]2[C:3]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[CH:11][C:4]=3[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=2)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Reactant: COc1ccc(B(O)O)cc1OC
Agent: O=Cc1cccc(B(O)O)c1
Product: COc1ccc(C2=NCC(=O)N(C)c3ccc(-c4ccccc4)cc32)cc1OC
Yield: 59 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 3,4-dimethoxyphenyl boronic acid. The title compound (88 mg) was obtained as a pale yellow solid, (yield=59%).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[C:4]=1[N:13]1[CH2:17][CH:16]([CH2:18][N:19]=[N+]=[N-])[O:15][C:14]1=[O:22])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[C:4]=1[N:13]1[CH2:17][CH:16]([CH2:18][NH2:19])[O:15][C:14]1=[O:22])[CH3:2]
Reactant: [H][H]
Reactant: CCc1ccc2nc(C)[nH]c2c1N1CC(CN=[N+]=[N-])OC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc2nc(C)[nH]c2c1N1CC(CN)OC1=O

Procedure:
A mixture of (±)-3-(5'-1-ethyl-2-methylbenzimidazolyl)-5-(azidomethyl)oxazolidin-2-one (XXXIX, EXAMPLE 70, 0.190 g) and palladium on carbon (10%, 0.065 g) is stirred in ethyl acetate (70 ml) for 15.5 hrs under 1 atm (balloon) hydrogen. The mixture is then filtered and the filtrate concentrated to give the crude product as a solid in an oil. The crude sample is placed on a silica gel column (5 cm×0.5 cm, 40-63μ) and eluted with ethyl acetate followed by methanol/ethyl acetate mixtures (1/9 10 ml, 1/3 20 ml, 1/1 20 ml. The 1/3 and 1/1 methanol/ethyl acetate fractions are combined and concentrated to give the title compound as a foamy solid. NMR (CDCl3, 300 MHz) 7.64, 7.55, 7.24, 4.70, 4.10, 3.87, 3.12, 3.01, 2.57 and 1.36 δ; CMR (CDCl3, 75.47 MHz) 13.60, 14.77, 38.46, 44.80, 48.61, 73.57, 109.06, 109.17, 114.63, 131.64, 132.86, 142.52, 152.02 and 155.09 δ.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH3:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:25]=1[O:32][CH3:33].Cl.C(=O)([O-])[O-].[NH4+:39].[NH4+]>C(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH3:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[NH:39])[NH2:31])=[CH:26][C:25]=1[O:32][CH3:33]
Reactant: [NH4+]
Reactant: COc1cc(C#N)ccc1NCc1nc2cc(N(C)S(=O)(=O)c3ccccc3)ccc2n1C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: COc1cc(C(=N)N)ccc1NCc1nc2cc(N(C)S(=O)(=O)c3ccccc3)ccc2n1C

Procedure:
Prepared analogously to Example 1e from 1-methyl-2-[N-(4-cyano-2-methoxy-phenyl)-aminomethyl]-5-(N-methyl-benzenesulphonylamino)-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH3:8][O:9][C:10]([N:12]([C:24]1[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:32]2[C:27]([CH:28]3[CH2:38][CH:29]3[CH2:30][O:31]2)=[CH:26][CH:25]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[NH2:23])(=[O:15])=[O:14])=[O:11].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:8][O:9][C:10]([N:12]([C:24]1[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:32]2[C:27]([CH:28]3[CH2:38][CH:29]3[CH2:30][O:31]2)=[CH:26][CH:25]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[NH:23][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])(=[O:14])=[O:15])=[O:11]
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2N)ccc2c1OCC1CC21
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2NC(=O)CCCCl)ccc2c1OCC1CC21
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.2 %

Procedure:
4-Chlorobutyryl chloride (3.0 g) was added to a stirred, cooled solution of methyl (1aRS,7bSR)-5-[N-(methoxycarbonyl)-N-(2-amino-4-fluorobenzenesulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 110, 0.135 g) and triethylamine (1.0 g) in THF (10 mL) at 0° C. On completion of the addition, the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether, with a gradient of 20-25% to give methyl (1aRS,7bSR)-5-{N-[methoxycarbonyl]-N-[2-(4-chlorobutyrylamino)-4-fluoro-benzenesulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.15 g) as a yellow oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=2)=O)[CH2:21][CH2:20]1.[OH-].[Na+]>C(OCC)C.O1CCCC1>[Cl:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]1[CH2:20][CH2:21][N:22]([CH2:25][C:27]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=2)[CH2:23][CH2:24]1
Reactant: COc1cc(C(=O)N2CCN(c3cccc(C)c3Cl)CC2)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(CN2CCN(c3cccc(C)c3Cl)CC2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
A solution of aluminum chloride (0.279 g, 2.09 mmol) in anhydrous diethyl ether (20 mL) is added dropwise to a suspension of lithium aluminum hydride (0.238 g, 6.27 mmol) in anhydrous tetrahydrofuran (20 mL) at 0° C. and stirred for 0.5 hour. To this mixture is added dropwise a solution of [4-(2-chloro-3-methylphenyl)piperazine-1-yl]-(3,4,5-trimethoxy-phenyl)methanone (2.12 g, 5.23 mmol) in anhydrous tetrahydrofuran (20 mL). The suspension is stirred for 2 hours at 0° C., followed by dropwise addition of 2N sodium hydroxide. The mixture is filtered through Celite and concentrated in vacuo. The resulting product is purified by MPLC on silica gel eluting with 40% ethyl acetate/hexane to give 1.74 g of the title compound as a white solid; mp 112-113° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1([C:13]([OH:15])=O)[CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O.[NH2:47][C:48]1[CH:81]=[CH:80][C:51]([O:52][C:53]2[CH:58]=[CH:57][N:56]=[C:55]3[N:59]([CH2:71][C:72]4[CH:77]=[CH:76][C:75]([O:78][CH3:79])=[CH:74][CH:73]=4)[N:60]=[C:61]([N:62]4[CH2:67][CH2:66][CH:65]([N:68]([CH3:70])[CH3:69])[CH2:64][CH2:63]4)[C:54]=23)=[C:50]([F:82])[CH:49]=1>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1([C:13]([NH:47][C:48]2[CH:81]=[CH:80][C:51]([O:52][C:53]3[CH:58]=[CH:57][N:56]=[C:55]4[N:59]([CH2:71][C:72]5[CH:73]=[CH:74][C:75]([O:78][CH3:79])=[CH:76][CH:77]=5)[N:60]=[C:61]([N:62]5[CH2:63][CH2:64][CH:65]([N:68]([CH3:70])[CH3:69])[CH2:66][CH2:67]5)[C:54]=34)=[C:50]([F:82])[CH:49]=2)=[O:15])[CH2:11][CH2:12]1
Reactant: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)C1(c2nc3ccccc3o2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(NC(=O)C5(c6nc7ccccc7o6)CC5)cc4F)ccnc32)cc1
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To a stirred solution of 1-(benzo[d]oxazol-2-yl)cyclopropanecarboxylic acid (3.8 mg, 0.019 mmol) in 150 μL dichloromethane at room temperature under nitrogen was added DIEA (8 μL, 0.047 mmol) followed by EDCI (4.5 mg, 0.024 mmol) and HOBT-H2O (3.6 mg, 0.024 mmol). After 15 minutes, a solution of 1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpiperidin-4-amine (7.7 mg, 0.016 mmol) (prepared in Example 93, Step A) in 150 μL dichloromethane was added. After stirring for 48 hours, the reaction was diluted to 30 mL with dichloromethane and washed with 10% sodium carbonate solution. The organics were dried (MgSO4), filtered and concentrated. The crude product was loaded onto a Biotage 12S column with dichloromethane and eluted with a step gradient of dichloromethane (100 mL), 2.5/97.5 MeOH/dichloromethane (100 mL) and 5/95 MeOH/dichloromethane to provide the desired product as a white foam (6.6 mg, 62% yield).