Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[C:19]([C:21]1([OH:29])[CH2:26][CH2:25][CH2:24][N:23]([CH3:27])[C:22]1=[O:28])#[CH:20]>>[OH:29][C:21]1([C:19]#[C:20][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:18]=2)[CH2:26][CH2:25][CH2:24][N:23]([CH3:27])[C:22]1=[O:28]
Reactant: C#CC1(O)CCCN(C)C1=O
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Product: CN1CCCC(O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)C1=O
Yield: 17 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 3-ethynyl-3-hydroxy-1-methylpiperidin-2-one (US2012/214762A1) to give the titled compound as a white solid (20 mg, 17%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([C:9]2[N:10]([CH2:26][CH3:27])[C:11]3[C:16]([C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:18])=[CH:15][N:14]=[CH:13][C:12]=3[N:25]=2)=[N:6][O:7][N:8]=1.O=[CH:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35]>ClCCCl>[C:34]([O:33][C:32](=[O:38])[NH:31][CH2:30][CH2:29][N:22]1[CH2:23][CH2:24][N:19]([C:17]([C:16]2[C:11]3[N:10]([CH2:26][CH3:27])[C:9]([C:5]4[C:4]([NH2:3])=[N:8][O:7][N:6]=4)=[N:25][C:12]=3[CH:13]=[N:14][CH:15]=2)=[O:18])[CH2:20][CH2:21]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: CCn1c(-c2nonc2N)nc2cncc(C(=O)N3CCNCC3)c21
Agent: Cl
Solvent: ClCCCl
Product: CCn1c(-c2nonc2N)nc2cncc(C(=O)N3CCN(CCNC(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of the free base from Example 250, Step 3 (prepared by eluting a sample of the dihydrochloride salt through an SCX cartridge using ammonia (10%) in ethanol) and tert-butyl N-(2-oxoethyl)carbamate (0.065 g, 0.41 mmol) in 1,2-dichloroethane (5 ml) was stirred at room temperature for 20 mins. This was then treated according to the method of Example 200 to afford the title compound; MS (ES+) m/e 486 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[C:24]([NH2:26])[S:25][C:21]=2[CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[C:24]([NH:26][C:14](=[O:16])[CH2:13][C:10]3[CH:9]=[CH:8][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[CH:12][CH:11]=3)[S:25][C:21]=2[CH:20]=1
Reactant: O=C(O)Cc1ccc(-c2ccncc2)cc1
Reactant: COc1ccc2nc(N)sc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2nc(NC(=O)Cc3ccc(-c4ccncc4)cc3)sc2c1

Procedure:
To a mixture of 2-(4-(pyridin-4-yl)phenyl)acetic acid 3-1 (45 mg, 0.21 mmol), 6-methoxybenzo[d]thiazol-2-amine 3-2 (36 mg, 0.20 mmol), and DIEA (32 mg, 0.25 mmol) in DMF (0.5 mL) under stirring was added HATU (84 mg, 0.22 mmol). The solution was stirred for 2 hours before it was subject to reverse phase HPLC for purification to give compound 3 as white solid. MS m/z 376.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 12.60 (s, 1H), 8.70 (m, 2H), 7.87 (m, 2H), 7.78 (m, 2H), 7.72 (d, 1H, J=8.8 Hz), 7.63 (d, 1H, J=2.8 Hz), 7.58 (m, 2H), 7.11 (dd, 1H, J1=8.8 Hz, J2=2.4 Hz), 3.96 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[C:8]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OC(=O)C)(=O)C>C(Cl)(Cl)Cl>[C:9]1([C:8]2[O:20][C:18](=[O:19])[C:17](=[CH:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1cccs1
Reactant: O=C(O)CCC(=O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C1OC(c2ccccc2)=CC1=Cc1cccs1
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
Thiophene-2-carboxaldehyde (27.4 cc), 3-benzoylpropionic acid (44.5 g), acetic anhydride (71 cc) and fused potassium acetate (20.5 g) are heated overnight at 80° C. The mixture is cooled to 40° C., chloroform is added and then poured onto crushed ice. Extraction is carried out with chloroform, the organic phase is washed with a decinormal sodium hydroxide solution, it is dried over magnesium sulfate and evaporated under reduced pressure. The residue is stirred for 45 minutes in 40°-60° petroleum spirit, filtered and dried. 5-Phenyl-3-(2-thienylmethylene)-2-furanone (45.3 g), m.p. 141° C., is thereby isolated.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:15])[N:9]([CH:12]2[CH2:14][CH2:13]2)[C:10]=1[CH3:11])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:12]1([N:9]2[C:10]([CH3:11])=[C:6]([CH2:4][OH:3])[N:7]=[C:8]2[CH3:15])[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1nc(C)n(C2CC2)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(CO)c(C)n1C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
Cyclopropyl-2,5-dimethyl-1H-imidazole-4-carboxylic acid ethyl ester (0.7 g, 3 mmol) was dissolved in 20 mL dry THF and cooled to 0° C. Lithium aluminum hydride (3.4 mL, 1M in THF, 3 mmol) was added dropwise and stirred for 1 h at 0° C. The reaction mixture was quenched with 0.13 ml of water, 0.13 ml of 4N sodium hydroxide and 0.4 ml of water. Sodium sulfate was added, stirred for 10 min, filtered and evaporated to dryness to obtain the desired compound as a light yellow solid (0.52 g, 93%), MS: m/e=167.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37]([C:39]1[N:40]([CH3:48])[C:41]2[C:46]([CH:47]=1)=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:25]3[CH:24]=[CH:23][C:22]([NH:36][C:37]([C:39]4[N:40]([CH3:48])[C:41]5[C:46]([CH:47]=4)=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])=[C:21]([O:20][CH3:19])[CH:26]=3)[C:3]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: Nc1ncnc2c1c(I)nn2-c1cc[n+]([O-])cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(-c3cc[n+]([O-])cc3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
A suspension of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyridiniumolate (0.500 g, 0.0014 mol) in dimethoxyethane (15 mL) and water (30 mL) was reacted with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.631 g, 0.00155 mol), sodium carbonate (0.374 g, 0.0035 mol) and tetrakis(triphenylphosphine) palladium (0) (0.163 g, 0.00014 mol) at 80° C. for 18 hours. The solid was filtered and washed with water. The solid was slurried in ethyl acetate for 18 hours and filtered, washing with ethyl acetate. The solid was dried in vacuo to give crude 4-[4-amino-3-(3-methoxy-4-[(1-methyl-1H-2-indolyl)-carbonyl]aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridiniumolate (0.523 g, 0.0010 mol) as a brown solid:
Reaction SMILES: [NH2:1][C:2]1[S:20][C:5]2[CH2:6][N:7](C(OCC3C=CC=CC=3)=O)[CH2:8][CH2:9][C:4]=2[C:3]=1[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1.NC1SC2CN(C(OCC3C=CC=CC=3)=O)CCC=2C=1C(=O)C1C=CC=CC=1>>[NH2:1][C:2]1[S:20][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCN(C(=O)OCc1ccccc1)C2
Agent: Nc1sc2c(c1C(=O)c1ccccc1)CCN(C(=O)OCc1ccccc1)C2
Product: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCNC2
Yield: 90 %

Procedure:
The procedure of Example 8 was followed except that a corresponding amount of 2-amino-3-(4-chloro-benzoyl)-6-benzyloxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, prepared as in Example 9, was used in place of 2-amino-3-benzoyl-6-benzyloxycarbonyl4,5,6,7-tetrahydrothieno[2,3-c]pyridine. (m.p. 164-166° C., 90% yield). 1H-NMR (CDCl3): 1.74 (m, 1 H); 1.89 (m, 2H); 2.84 (t, 2H); 3.82 (s, 2H); 6.85(sb, 2H), 7.29-7.48 (m, 5H).
Reaction SMILES: CO[C:3]([C:5]1[NH:6][C:7]2[CH:8]=[C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:10]=[C:11]3[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]=1[C:12]=23)=O.[CH2:27]([Sn](CCCC)(CCCC)C=C)CCC>CN(C)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>[C:23]([O:22][C:20](=[O:21])[NH:19][C:9]1[CH:10]=[C:11]2[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]3=[C:5]([CH:3]=[CH2:27])[NH:6][C:7]([CH:8]=1)=[C:12]23)([CH3:25])([CH3:26])[CH3:24]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Yield: 83.5 %

Procedure:
Under an argon atmosphere, Intermediate 147(d) of Example 147 (0.250 g, 0.661 mmol), tributyl-vinyl-tin (0.420 g, 1.32 mmol) and tetrakis(triphenylphosphine)palladium(0) (38 mg, 0.033 mmol) in anhydrous N,N-dimethylformamide (5 mL) were heated at 85° C. for 16 hours. The reaction was filtered through a thin pack of diatomaceous earth, and the filtrate concentrated in vacuo. Silica gel chromatography (eluted with 1:4 ethyl acetate: dichloromethane) afforded the title compound (0.18 g, 0.552 mmol) as a yellow powder in 84% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1S[CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[CH:23]=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8].C[O:28]C(C1OC=CC=1NC1C2C=CNC=2N=CN=1)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[O:28][CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[CH:23]=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8]
Reactant: COC(=O)c1occc1Nc1ncnc2[nH]ccc12
Reactant: O=C(NCc1cccc(Cl)c1)c1sccc1Nc1ncnc2[nH]ccc12
Product: O=C(NCc1cccc(Cl)c1)c1occc1Nc1ncnc2[nH]ccc12
Yield: 9 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid 3-chloro-benzylamide using 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-furan-2-carboxylic acid methyl ester instead of 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester and obtained in 9% yield. 1H NMR (DMSO-d6) 11.97 (br s, 1H), 9.67 (s, 1H), 9.01 (t, J=6.2 Hz, 1H), 8.38 (s, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.41-7.30 (m, 5H), 6.45 (d, J=2.2 Hz, 1H), 4.49 (d, J=5.9 Hz, 2H); MS (m/z) 368 [M+H]+ (35Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][N:11]1[N:15]=[N:14][CH:13]=[N:12]1.[CH:17](Br)([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:10][N:11]1[N:15]=[N:14][CH:13]=[N:12]1
Reactant: CC(C)Br
Reactant: O=C(Cn1ncnn1)c1ccc(Cl)cc1Cl
Product: CC(C)OC(=Cn1ncnn1)c1ccc(Cl)cc1Cl

Procedure:
Analogously to Example 7a,b, after reacting 1-(2,4-dichlorophenyl)-2-tetrazol-2-yl-ethanone with isopropyl bromide there was obtained 2-[2-(2,4-dichloro-phenyl)-2-isopropoxy-vinyl]-2H-tetrazole as a colourless oil. [M]+=299.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](B(O)O)[CH:10]=2)[O:5][C:4]([CH3:16])([CH3:15])[CH2:3]1.Br[C:18]1[C:23](=[O:24])[N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:28][CH:27]=2)[C:21]([CH2:40][CH2:41][CH3:42])=[N:20][C:19]=1[CH2:43][CH3:44]>O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:43]([C:19]1[N:20]=[C:21]([CH2:40][CH2:41][CH3:42])[N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:28][CH:27]=2)[C:23](=[O:24])[C:18]=1[C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][C:4]([CH3:16])([CH3:15])[CH2:3][CH:2]2[OH:1])[CH3:44]
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)CC(O)c2cc(B(O)O)ccc2O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCc1nc(CC)c(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A mixture of (4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)boronic acid (1.1 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.14 g) and 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1.5 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (4 mL) was stirred overnight at 100° C. under an argon atmosphere. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.5 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.[F:24][CH:25]([F:29])[C:26](O)=[O:27]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:26](=[O:27])[CH:25]([F:29])[F:24])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: O=C(O)C(F)F
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Product: O=C(C(F)F)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
5-Chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide and difluoroacetic acid
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:6]([CH:18]=1)[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:8].[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:5]2[CH:4]=[CH:3][C:2]([C:32]3[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=3)=[CH:18][C:6]=2[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:8])=[CH:22][CH:23]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(OCc1ccc(F)cc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)OCc3ccc(F)cc3)c2)cn1
Temperature: 90 °C

Procedure:
A mixture of (4-fluorophenyl)methyl 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}benzoate (420 mg, 0.97 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (208 mg, 1.00 mmol), tetrakis(triphenylphosphine)palladium(0) (34.7 mg, 0.03 mmol) and K2CO3 (414 mg, 3 mmol) in 1,4-dioxane (10 ml) and water (2 ml) was stirred under nitrogen and heated at 90° C. for 16 hours. The solvent was removed, and the residue was dissolved in ethyl acetate (100 ml) and filtered. The filtrate was washed with water (50 ml) and brine (50 ml), dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by a silica gel column (eluting with dichloromethane/methanol=50:1) yield the title compound as a white solid. 360 mg.
Reaction SMILES: C([O:8][C:9](=[O:33])[C@@H:10]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:11][CH2:12][C:13]1[N:14](CC2C=CC=CC=2)[NH:15][NH:16][N:17]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[C:29]([O:28][C:26]([NH:25][C@@H:10]([CH2:11][CH2:12][C:13]1[N:14]=[N:15][NH:16][N:17]=1)[C:9]([OH:33])=[O:8])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC1=NNNN1Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCc1nn[nH]n1)C(=O)O
Reaction time: 48 h

Procedure:
To a solution of 786 mg (S)-4-(4-benzyl-2H-tetrazol-5-yl)-2-tert-butoxycarbonylamino-butyric acid benzyl ester in 20 ml ethyl acetate was added 1.0 g Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (1 bar) for 48 h. The reaction mixture was filtrated over a plug of Celite® and washed with ethyl acetate. Yield: 516 mg colorless solid
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][CH:6]([N:8]2[CH2:11][CH2:10][CH:9]2[C:12]([O:14]C)=[O:13])[CH2:5][CH2:4][O:3]1.O.[OH-].[Li+:19]>>[CH3:1][C:2]1([CH3:16])[CH2:7][CH:6]([N:8]2[CH2:11][CH2:10][CH:9]2[C:12]([O-:14])=[O:13])[CH2:5][CH2:4][O:3]1.[Li+:19]
Reactant: COC(=O)C1CCN1C1CCOC(C)(C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CC(N2CCC2C(=O)[O-])CCO1
Yield: 72 %

Procedure:
The reaction of methyl 1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)azetidine-2-carboxylate 19H and lithium hydroxide monohydrate yielded lithium 1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)azetidine-2-carboxylate as an off-white solid (72%). MS ISP (m/e): 212.1 (100) [(M+H)]+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:8]=2[CH2:7][CH2:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:15]([N:11]1[C:12]2[CH2:13][CH2:14][N:5]([CH2:4][CH2:3][OH:2])[CH2:6][CH2:7][C:8]=2[C:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[N:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CN1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccccc3)c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCN1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
To a solution of [1-benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulen-6-yl]-acetic acid methyl ester (Example 170, 16 mg) in THF (1 mL) was added lithium aluminum hydride (100 mg). The mixture was stirred at RT for 16 h. The reaction was quenched by the addition of H2O (0.1 mL). Concentration and purification (SiO2, 2 M NH3 in MeOH/CH2Cl2) provided the title compound (5 mg). MS (ESI): exact mass calculated for C22H24ClN3O, 381.16; found, m/z 382.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.50-7.20 (m, 7H), 7.04 (d, J=7.2 Hz, 1H), 5.29 (s, 2H), 3.07-3.04 (m, 2H), 2.89-2.77 (m, 10H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([NH2:10])[CH2:5]1)(=[O:3])[CH3:2].C(O[CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)(=O)C>C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([NH:10][CH:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[C:28]2=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCC(N)C1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: Cc1ccccc1
Product: CC(=O)N1CCCC(NC2c3ccccc3Oc3ccccc32)C1

Procedure:
Refluxing 1-acetyl-3-aminopiperidine with 9-acetoxyxanthene in dry toluene by the procedure of Example 1 gives N-(N-acetyl-3-piperidinyl)-9-xanthenylamine.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:8][N:7]1[C:3]([CH2:2][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([CH2:2][C:3]3[N:7]([CH3:8])[N:6]=[C:5]([C:9]4[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=4)[CH:4]=3)[CH2:23][CH2:22]2)=[CH:4][C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:6]1
Reactant: C1CNCCNC1
Reactant: COc1cc(-c2cc(CCl)n(C)n2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)nn4C)CC3)n(C)n2)cc(OC)c1OC

Procedure:
5-Chloromethyl-1-methyl-3-(3,4,5-trimethoxy-phenyl)pyrazole (119 mg) and homopiperazine (20 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [N:1]([CH:4]([CH:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][CH2:23][C:22]2[CH:31]=[CH:32][CH:33]=[CH:34][C:21]1=2)[C:5](N1C(C)C(C2C=CC=CC=2)OC1=O)=[O:6])=[N+:2]=[N-:3].[OH-:35].[Li+].OO.S([O-])([O-])=O.[Na+].[Na+]>O.O1CCCC1>[N:1]([C@H:4]([CH:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][CH2:23][C:22]2[CH:31]=[CH:32][CH:33]=[CH:34][C:21]1=2)[C:5]([OH:6])=[O:35])=[N+:2]=[N-:3]
Reactant: CC1C(c2ccccc2)OC(=O)N1C(=O)C(N=[N+]=[N-])C1c2ccccc2CCc2ccccc21
Reactant: [OH-]
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@@H](C(=O)O)C1c2ccccc2CCc2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of [4R-[3(R*),4α,5α]]-3 [azido(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)acetyl]-4-methyl5-phenyl-2-oxazolidinone (13.7 g, 30.27 mmol) in 4:1 tetrahydrofuran water (300 mL) at 0° C., is added a solution of lithium hydroxide (2.5 g, 60.54 mmol) in hydrogen peroxide (17.2 mL, 151.35 mmol, 30% aqueous) dropwise under nitrogen. The milky mixture is stirred at 0° C. for 1 hour. Aqueous sodium sulfite (50 mL) is added. The bulk o the tetrahydrofuran is evaporated in vacuo. The aqueous solution is cooled in an ice bath and acidified with 6N hydrochloric acid to pH 1. The white solid is extracted with dichloromethane (5X) and dried (magnesium sulfate). Evaporation of solvent in vacuo gives a yellow oil, which is purified by flash chromatography (silica gel, hexane ethyl acetate acetic acid/100:50:1) to yield the title compound as a white solid, 8.3 g; mp 101°-102° C., [α]D =-38.7° (c=1.0, methanol). The chiral auxiliary ((4R)-methyl-(5S) phenyl-2-oxazolidinone) is recovered as a white solid, 5.2 g; mp 120°-122° C.
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12](=[O:18])(=[O:17])[NH:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=[C:7]([F:19])[C:3]=1[C:4]([OH:6])=O.[NH:20]1[C:24]2=[N:25][CH:26]=[C:27]([NH2:29])[CH:28]=[C:23]2[CH:22]=[CH:21]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:10]([NH:11][S:12](=[O:18])(=[O:17])[NH:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=[C:7]([F:19])[C:3]=1[C:4]([NH:29][C:27]1[CH:28]=[C:23]2[CH:22]=[CH:21][NH:20][C:24]2=[N:25][CH:26]=1)=[O:6]
Reactant: Nc1cnc2[nH]ccc2c1
Reactant: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
2,6-Difluoro-3-(N-propylsulfamoylamino)benzoic acid (0.095 g, 0.32 mmol), 1H-pyrrolo[2,3-b]pyridin-5-amine (0.043 g, 0.32 mmol), HOBt (0.044 g, 0.32 mmol), and EDCI (0.062 g, 0.32 mmol) were dissolved in DMF (1.6 mL) and stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (30 mL) and washed with a mixture of 1:1:1 water:bicarbonate:brine (3×20 mL). The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via column chromatography eluting with 1:1 then 8:2 EtOAc:hexanes to provide 2,6-difluoro-3-(N-propylsulfamoylamino)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.060 g, 0.15 mmol, 45% yield). 1H NMR (400 MHz, CD3OD) δ 8.36-8.40 (m, 2H), 7.64-7.72 (m, 1H), 7.41-7.43 (m, 1H), 7.06-7.13 (m, 1H), 6.50-6.52 (m, 1H), 2.96-3.02 (m, 2H), 1.47-1.57 (m, 2H), 0.87-0.93 (m, 3H); m/z (APCI-pos) M+1=410.2.