Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3([CH3:27])[C:18]4[CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=[CH:22][C:17]=4[O:16][CH2:15]3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].[OH-].[Li+]>>[CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3([CH3:27])[C:18]4[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=[CH:22][C:17]=4[O:16][CH2:15]3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(C)(c1ccc3c(c1)C(C)(C)CCC3(C)C)CO2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCC(C)(C)c2cc(C3(C)COc4ccc(C(=O)O)cc43)ccc21
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of methyl 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-(3-methyl)-2,3-dihydrobenzofuran-5-carboxylate (510 mg, 135 mmol), sodium hydroxide (0.33 g, 7.9 mmol), and lithium hydroxide (0.33 g, 7.9 mmol) is stirred 5 days at ambient temperature. It is concentrated in vacuo at 40° C. in a rotary evaporator. 10 ml of water and 10 ml of ethyl acetate are added again. The mixture is acidified to pH 1 with a concentrated hydrochloric acid solution. After separation, the organic phase is washed twice with 10 ml of water, dried over magnesium sulphate, and concentrated in vacuo at 40° C. in a rotary evaporator. The solid obtained is washed with heptane.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:21])/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>ClCCl>[OH:23][N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12](=[O:21])/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Nc1ccccc1
Reactant: O=C/C=C/c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(/C=C/c1ccccc1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of (E)-cinnamaldehyde (132 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:15][O:16][CH2:17][C:18](Cl)=[O:19]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:15][O:16][CH2:17][C:18]([N:8]1[C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[O:12][CH2:11][CH2:10][CH2:9]1)=[O:19]
Reactant: COCC(=O)Cl
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCCN2
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COCC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (203 mg, 1.04 mmol) and 4-Dimethylaminopyridine (13 mg, 0.10 mmol) in Pyridine (3.5 mL) was treated with Methoxyacetyl chloride (0.15 mL, 1.6 mmol) was added to the vial and stirred at rt. After 4 h, the mixture was partitioned between EtOAc and water, separated and the org. layer was washed with 1N HCl. After washing with brine and drying, 2-Methoxy-1-(3-nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone was isolated following silica gel chromatography (0-100% EtOAc:Hex) as yellow solids (270 mg, 97%). 1H-NMR (CDCl3): 7.96 (m, 2H), 7.36 (m, 1H), 4.82 (m, 1H), 4.25 (m, 2H), 3.89 (m, 3H), 3.34 (s, 3H), 2.96 (m, 1H), 2.13 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30](Br)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:40]([N:42]([CH2:59][CH3:60])[CH2:43][CH2:44][N:45]1[CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:47]=[N:46]1)[CH3:41]>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([C:48]4[CH:47]=[N:46][N:45]([CH2:44][CH2:43][N:42]([CH2:59][CH3:60])[CH2:40][CH3:41])[CH:49]=4)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Reactant: CCN(CC)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCN(CC)CC)c4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure of Example 97 using diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate and N,N-diethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanamine (Compound 175A). MS (ES+): m/z 715.47 (100) [MH+]; HPLC: tR=0.75 min (UPLC, purity).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N+:13]([O-:28])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1ccnc2ccccc12)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOP(=O)(Cc1cc[n+]([O-])c2ccccc12)OCC
Reaction time: 0.75 h

Procedure:
To a solution of 5.7 g of 4-(diethylphosphonomethyl)quinoline in 100 ml of methylene chloride at room temperature is added 3.2 g of m-chloroperbenzoic acid. After reacting for 45 minutes, an additional 1.5 g portion of m-chloroperbenzoic acid is added, and the reaction mixture is stirred for one hour. The reaction mixture is washed with saturated potassium carbonate solution, dried over sodium sulfate and evaporated to dryness to give 4-(diethylphosphonomethyl)-quinoline-N-oxide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=S)[CH3:2].Cl.Cl.[NH2:17][CH:18]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:19]([NH:21][C:22]1([C:32]#[N:33])[CH2:26][CH2:25][N:24]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:23]1)=[O:20]>>[CH2:1]([O:3][C:4](=[O:14])[N:5]=[C:6]([NH:17][CH:18]([C:19](=[O:20])[NH:21][C:22]1([C:32]#[N:33])[CH2:26][CH2:25][N:24]([CH:27]([CH2:28][CH3:29])[CH2:30][CH3:31])[CH2:23]1)[CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOC(=O)NC(=S)N1CCOCC1
Reactant: CCC(CC)N1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)C1
Agent: Cl
Product: CCOC(=O)N=C(NC(CC1CCCCC1)C(=O)NC1(C#N)CCN(C(CC)CC)C1)N1CCOCC1

Procedure:
The title compound was prepared starting from (morpholine-4-carbothioyl)-carbamic acid ethyl ester and 2-amino-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 5, step b, . MS, m/z 519=M+1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[S:16]1[CH2:18][CH2:17]1>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:18][CH2:17][SH:16])[CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: C1CS1
Solvent: CN(C)C=O
Product: SCCN1CCN(c2cccc3[nH]ccc23)CC1
Yield: 43.4 %

Procedure:
1-(1H-Indol-4-yl)piperazine (3.9 g) and thiirane (1.75 g) was dissolved in DMF (200 mL) and refluxed for 1 h. The mixture was evaporated and re-dissolved in TBF, dried with MgSO4, filtered and evaporated to give the an oil which was subjected to purification by column chromatography (silica gel; ethyl acetate and heptane) giving the title compound as an oil (2,2 g). MS m/z (%): 261 (MH+, 100%), 202 (100%), 159 (23%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[NH:34][CH3:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[N:34]([CH3:35])[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:23])([F:24])[F:25])[CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1ccc(F)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccc(F)cc1F

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (100 mg, 0.24 mmol), (2,4-difluoro-phenyl)-methyl-amine (103 mg, 0.72 mmol), BOP (137 mg, 0.31 mmol), DIEA (265 μL, 1.44 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (2,4-difluoro-phenyl)-methyl-amide: MS m/z: (M+H) 541.0.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:21]3[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=3[C:16]([O:24][CH:25]([F:27])[F:26])=[CH:15][CH:14]=2)=[O:12])=CC=1)([O-])=O.[NH2:28][C:29]1[N:33]([CH3:34])[CH:32]=[N:31][C:30]=1[C:35]#[N:36]>C(OCC)C>[C:35]([C:30]1[N:31]=[CH:32][N:33]([CH3:34])[C:29]=1[NH:28][C:11]([C:13]1[C:21]2[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=2[C:16]([O:24][CH:25]([F:26])[F:27])=[CH:15][CH:14]=1)=[O:12])#[N:36]
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)Oc3ccc([N+](=O)[O-])cc3)c2o1
Reactant: Cn1cnc(C#N)c1N
Solvent: CCOCC
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3c(C#N)ncn3C)c2o1
Yield: 34.6 %

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid 4-nitro-phenyl ester (100 mg) and 5-amino-1-methyl-1H-imidazole-4-carbonitrile (65 mg). Purification by column chromatography on silica eluting with 0-5% methanol in ethyl acetate afforded, after trituration with diethyl ether, the title compound as a white solid (33 mg)
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:10]=[C:11]([CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[C:21](O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:21][O:19][C:18](=[O:20])[CH2:17][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([Br:8])[CH:10]=1
Reactant: CC(=O)O
Reactant: COc1ccc(CC(=O)O)cc1Br
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Trimethylsilyldiazomethane (2 M solution in diethyl ether, 0.306 mL, 0.612 mmol) was added to a solution of (3-bromo-4-methoxy-phenyl)-acetic acid (100 mg, 0.408 mmol) in methanol (1 mL) and toluene (4 mL), and the mixture was stirred at room temperature for 10 minutes. Acetic acid was added to the reaction mixture to terminate the reaction, and then the mixture was concentrated under reduced pressure to give the target compound as a colorless oil (100 mg, 95%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C@H:20]4[CH2:24][CH2:23][CH2:22][O:21]4)[CH:14]=3)[C:9]2=[O:25])=[CH:4][C:3]=1[F:26].[CH3:27][O:28][C@@H:29]1[CH2:33][NH:32][CH2:31][C@H:30]1[N:34]([CH3:36])[CH3:35]>>[CH3:35][N:34]([CH3:36])[C@H:30]1[C@H:29]([O:28][CH3:27])[CH2:33][N:32]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C@H:20]5[CH2:24][CH2:23][CH2:22][O:21]5)[CH:14]=4)[C:9]3=[O:25])=[CH:4][C:3]=2[F:26])[CH2:31]1
Reactant: O=c1c2ccc(OC[C@H]3CCCO3)cc2ccn1-c1ccc(Br)c(F)c1
Reactant: CO[C@@H]1CNC[C@H]1N(C)C
Product: CO[C@@H]1CN(c2ccc(-n3ccc4cc(OC[C@H]5CCCO5)ccc4c3=O)cc2F)C[C@H]1N(C)C

Procedure:
2-(4-Bromo-3-fluorophenyl)-6-[(R)-1-(tetrahydrofuran-2-yl)methoxy]-2H-isoquinolin-1-one and ((3R*,4R*)-4-methoxy-pyrrolidin-3yl)-dimethylamine were reacted according to Method R1. In this way the product was obtained with molecular weight 481.57 (C27H32FN3O4); MS (ESI): 482 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[CH:8]=[C:7]3[O:14][CH2:15][O:16][C:6]3=[CH:5][C:4]=2[N:3]=1.[CH2:17]([NH2:19])[CH3:18].Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.C1COCC1>[CH2:17]([NH:19][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[CH:8]=[C:7]3[O:14][CH2:15][O:16][C:6]3=[CH:5][C:4]=2[N:3]=1)[CH3:18]
Reactant: O=Cc1cc2cc3c(cc2nc1Cl)OCO3
Reactant: CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCNc1nc2cc3c(cc2cc1C=O)OCO3
Temperature: 160 °C
Yield: 91 %

Procedure:
To a solution of 6-chloro-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde (1.0 g, 4.24 mmol) in dioxane (10 mL) was added ethylamine (3.58 mL, 70% in water) and the mixture was heated at 160° C. under microwave irradiation for 45 min. After cooling to RT, the mixture was poured into a mixture of THF:1 N HCl aq. solution=1:1 (25 mL) and stirred for 25 min at RT. The mixture was brought to pH=7 with a saturated aq. solution of NaHCO3 and extracted with CH2Cl2 (50 mL). The organic layer was washed with H2O (3×30 mL), brine (30 mL), dried over Na2SO4, filtered and evaporated to give 6-(ethylamino)-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde RBO 35180 as a yellow solid (941 mg, 91% yield).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25]([OH:27])=O)(=[O:3])[NH2:2].[CH3:28][N:29]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30]1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:34][CH:31]4[CH2:32][CH2:33][N:29]([CH3:28])[CH2:30]4)=[O:27])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CN1CCC(N)C1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Product: CN1CCC(NC(=O)c2c(C(N)=O)nc3n2CCOc2cc(F)c(C#CC(C)(C)O)cc2-3)C1

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.06 g) was reacted with 1-methylpyrrolidin-3-amine similar to as described in Example 2 to afford 15.9 mg of (±)9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(1-methylpyrrolidin-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 456 (M)+. 1H NMR (400 MHz, DMSO) δ 11.49 (d, J=6.5 Hz, 1H), 8.59 (d, J=8.5 Hz, 1H), 8.35 (s, 1H), 7.84 (s, 1H), 7.01 (d, J=10.6 Hz, 1H), 5.48 (s, 1H), 5.07-4.91 (m, 2H), 4.62-4.45 (m, 2H), 4.42-4.24 (m, 1H), 2.75-2.67 (m, 1H), 2.64-2.55 (m, 1H), 2.43-2.34 (m, 2H), 2.24-2.14 (m, 1H), 1.68-1.56 (m, 1H), 1.50 (s, 6H).
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]4[CH:25]=[C:26]([CH:39]=[CH:40][CH:41]=4)[CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH2:18][CH2:17]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:17][CH2:18][N:19]([CH2:22][CH2:23][C:24]4[CH:25]=[C:26]([CH:39]=[CH:40][CH:41]=4)[CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:20][CH2:21]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCOCCC(=O)OC(C)(C)C)c4)CC3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCOCCC(=O)O)c4)CC3)C2)cs1
Reaction time: 18 h

Procedure:
tert-Butyl 3-(3-(2-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanoate [Example 34, step b] (0.70 g) was stirred in dichloromethane (8 mL) and trifluoroacetic acid (2 mL) was added. The solution was stirred for 18 hours, then the volatiles were removed under reduced pressure to afford the subtitled compound. Yield 1.0 g.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])=[C:2]=[O:3].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][NH:22][CH3:23])=[CH:15][CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][N:22]([CH3:23])[C:2]([NH:1][C:4]2[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[CH:5]=2)=[O:3])=[CH:17][CH:18]=1
Reactant: CNCCCc1ccc(Br)cc1
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: CN(CCCc1ccc(Br)cc1)C(=O)Nc1cccc(C#N)c1
Reaction time: 8 h
Yield: 82.5 %

Procedure:
3-Isocyanatobenzonitrile (202 mg, 1.4 mmol) was added in one portion to a solution of 22B (320 mg, 1.4 mmol) in methylene chloride (10 mL). After stirring overnight the reaction mixture was concentrated in vacuo and purified by flash chromatography (0 to 100% EtOAc in hexanes) to yield 22C (430 mg, 88%) as a clear oil. MS (ESI) m/z 371.92/373.92 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[CH:24])=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1)[C:23]#[CH:24]
Reactant: C#CCOc1ccc(OCC2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: C#CCOc1ccc(OC[C@H]2CCCN2)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of the product from step 3 (100 mg) was added 2M HCl in dioxane (4 mL) and the resulting mixture was stirred for 2 h, and the solvent was removed in vacuo. Crude material was triturated with ether to obtain the title product (70 mg, 100%); LCMS; 97%, m/z 232.1 (M+1); 1H NMR (DMSO-d6, 400 MHz) δ 1.70 (1H, m), 1.95 (2H, m), 2.10 (2H, m), 3.20 (2H, m), 3.53 (2H, m), 3.86 (1H, m), 4.07 (1H, dd, J1=8.0 Hz, J2=10.0 Hz), 4.18 (1H, dd, J1=4.0 Hz, J2=10.8 Hz), 6.94 (4H, s), 9.2 (2H, br s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[OH:11])=[CH:6][C:5]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.O([Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[O:11][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])=[CH:6][C:5]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(C(O)c2ccncc2)cc1-c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(O[Si](C)(C)C(C)(C)C)c2ccncc2)cc1-c1ccccc1
Reaction time: 18 h
Yield: 93 %

Procedure:
4-(4-Pyridylhydroxymethyl)-2-phenylbenzoic acid methyl ester (769 mg, 2.41 mmol), prepared as in Example 297A, diisopropylethylamine (0.84 mL, 4.8 mmol), and t-butyldimethylsilyl triflate (1.1 mL, 4.8 mmol) were dissolved in methylene chloride (50 mL) and stirred for 18 hours. TLC indicated the presence of the alcohol so additional base (1 mL) and triflate (0.5 mL) were added. After 15 minutes, all starting alcohol was consumed. The reaction mixture was washed with water, 5% NaHCO3, and brine, dried over Na2SO4, and concentrated. Chromatography on silica gel (20% ethyl acetate-hexane) provided the desired compound in a 93% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.O=[S:20](Cl)Cl>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4]([CH:3]=1)=[N:9][S:20][N:8]=2
Reactant: Nc1ccc(Br)cc1N
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccc2nsnc2c1
Temperature: 25 °C

Procedure:
To a solution of 4-bromobenzene-1,2-diamine (5.236 g, 28.0 mmol) and Hunig's base (19.5 mL, 112 mmol) in dichloromethane (160 mL) was added SOCl2 (4.08 mL, 56 mmol) dropwise at room temperature. The resulting reaction mixture was heated to reflux overnight. The reaction mixture was then allowed to cool to room temperature, and quenched with 10% HCl until pH=2. The resulting mixture was extracted with dichloromethane (200 mL×4), dried over Na2SO4 and concentrated. The crude compound was purified by flash column chromatography (silica gel, chloroform) to afford 5-bromobenzo[1,2,5]thiadiazole as a brown solid which was used directly in the next step. 1H NMR (CDCl3 500 MHz): δ: 8.21 (d, 1H, J=1.5 Hz), 7.87 (d, 1H, J=8.5 Hz), 7.69 (dd, 1H, J=8.5, 1.5 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC>[Br:9][C:10]1[CH:14]=[CH:13][N:12]([C:2]2[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[N:11]=1
Reactant: Clc1cccnc1Cl
Reactant: Brc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Clc1cccnc1-n1ccc(Br)n1
Temperature: 125 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2,3-dichloropyridine (27.4 g, 185 mmol) and 3-bromopyrazole (i.e. the product of Step B) (25.4 g, 176 mmol) in dry N,N-dimethylformamide (88 mL) was added potassium carbonate (48.6 g, 352 mmol), and the reaction mixture was heated to 125° C. for 18 hours. The reaction mixture was cooled to room temperature and poured into ice water (800 mL). A precipitate formed. The precipitated solids were stirred for 1.5 hrs, filtered and washed with water (2×100 mL). The solid fiber cake was taken up in methylene chloride and washed separately with water, 1 N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine. The organic extracts were then dried over magnesium sulfate and concentrated to afford 39.9 g of a pink sold. The crude solid was suspended in hexane and stirred vigorously for 1 hr. The solids were filtered, washed with hexane and dried to afford the title product as an off-white powder (30.4 g) determined to be >94% pure by NMR. This material was used without further purification in Step D.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][N:5]=1)[CH3:2].Br[C:20]1[N:25]2[CH:26]=[CH:27][N:28]=[C:24]2[C:23]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[CH:32][CH:31]=2)=[N:22][CH:21]=1.CC([O-])(C)C.[Na+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:42][N:39]1[CH2:40][CH2:41][N:36]([C:33]2[CH:34]=[CH:35][C:30]([NH:29][C:23]3[C:24]4[N:25]([CH:26]=[CH:27][N:28]=4)[C:20]([C:8]4[CH:7]=[CH:6][N:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=4)=[CH:21][N:22]=3)=[CH:31][CH:32]=2)[CH2:37][CH2:38]1
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(-c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)c3nccn23)ccn1
Temperature: 85 °C

Procedure:
A mixture of 2-ethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (97 mg, 0.31 mmol), (5-bromoimidazo[1,2-a]pyrazin-8-yl)-(4-(4-methylpiperazin-1-yl)phenyl)amine (100 mg, 0.259 mmol), Pd(PPh3)4 (29 mg, 0.026 mmol) and NaOtBu (99 mg, 1.0 mmol) in DMF (3 mL) and water (1 mL) is heated at 85° C. for 18 hours. After this time the reaction mixture is cooled to room temperature and the solvents removed in vacuo. The residue is chromatographed on silica gel, eluting with DCM followed by 96:4 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated to afford the title ethoxypyridine as a solid.