Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[NH2:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 31.1 %

Procedure:
Following general procedure D, (S)-tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.17 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (75 mg, 0.26 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (29 mg, 31% over 2 steps) as a light orange solid: 1H NMR (500 MHz, MeOD+TFA-d) δ 9.40 (br s, 1H), 8.25-8.19 (m, 2H), 8.11 (br s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.65 (dd, J=9.1, 2.8 Hz, 1H), 7.32 (s, 2H), 7.7 (d, J=9.1 Hz, 1H), 4.53 (br s, 1H), 4.00 (dt, J=12.8, 4.0 Hz, 1H), 3.39-3.23 (m, 3H), 2.86 (br s, 1H), 2.22-2.12 (m, 1H), 1.98-1.88 (m, 1H), 1.78-1.64 (m, 2H), 1.26-1.16 (m, 4H). ESI MS m/z 548 [C29H27Cl2N5O2+H]+; HPLC>99.0% (AUC), tR=10.97 min.
Reaction SMILES: [N:1]1([C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CO.O1CCOCC1>[NH:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([C:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2CCCC2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C([C@@H]1CCCNC1)N1CCCC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate in methanol (120 mL) was slowly added a solution of hydrogen chloride in 1,4-dioxane (30 mL, 4M). The mixture was stirred at 30° C. for 2 h. The solvent was removed under reduced pressure to afford (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone, which was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH2:31])(=[O:30])=[O:29]>ClCCl.N1C=CC=CC=1>[NH2:31][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH2:31])(=[O:29])=[O:30])=[O:13])(=[O:29])=[O:30]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccccc1S(N)(=O)=O
Temperature: 23 °C
Reaction time: 144 h
Yield: 19.6 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 2-aminobenzenesulfonamide (2.00 g, 11.6 mmol) in 16 mL of pyridine. The reaction mixture was stirred for 6 days at 23° C. under nitrogen atmosphere. The crude product was recrystallized from acetonitrile to yield 0.70 g of the title compound, mp 150°-151° C. (dec.).
Reaction SMILES: [N:1]1[C:6]2[CH2:7][NH:8][CH2:9][C:5]=2[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[O:21])[CH:15]=[CH:14]3)=[N:3][CH:2]=1.Br[CH2:34][CH2:35][OH:36]>CN(C=O)C>[OH:36][CH2:35][CH2:34][N:8]1[CH2:9][C:5]2[C:4]([O:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=3)=[O:21])[CH:15]=[CH:14]4)=[N:3][CH:2]=[N:1][C:6]=2[CH2:7]1
Reactant: OCCBr
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ncnc4c3CNC4)ccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ncnc4c3CN(CCO)C4)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide (125.9 mg, 0.287 mmol) is dissolved in DMF (5 mL) and TEA (80 μL, 0.577 mmol) is added followed by 2-bromoethanol (80 μL, 1.133 mmol). The solution is stirred at rt overnight. Then the reaction is concentrated and absorbed onto silica gel and separated via FCC (0-10%, 10% NH4 in MeOH:DCM) to obtain 5-(6-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide. MS (ESI) m/z 484.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.38 (s, 1H) 8.56 (s, 1H) 8.27 (d, J=9.09 Hz, 1H) 8.09-8.14 (m, 2H) 7.97 (d, J=7.58 Hz, 1H) 7.65 (t, J=8.08 Hz, 1H) 7.48-7.52 (m, 2H) 7.15 (dd, J=8.84, 2.53 Hz, 1H) 6.80 (d, J=3.54 Hz, 1H) 4.57 (t, J=5.56 Hz, 1H) 3.98-4.03 (m, 4H) 3.58 (q, J=6.06 Hz, 2H) 2.82 (t, J=6.06 Hz, 2H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>ClCCl>[C:35]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:17][CH2:18]2)=[CH:6][CH:5]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
To a stirred solution of 0.38 g (1 mmol) of N-(4-amino-phenyl)-2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-acetamide dihydrochloride (Example 181) and 0.28 ml (2 mmol) of triethylamine in 10 ml of dichloromethane 0.1 ml (1 mmol) of acetic anhydride in 2 ml of dichloromethane is added dropwise below 10° C., and the reaction mixture is stirred at room temperature for 3 hours. The solvent is evaporated and the residue is treated with water and the crystals are filtered off to yield 0.15 g (39%) of the title compound. Melting Point: 173-180° C. (water)
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25]CC)=O)[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: C1CCNC1
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCC2)no1
Temperature: 60 °C
Yield: 112.9 %

Procedure:
A solution of ethyl 5-{(1R)-1 -[2-(tert-butoxy)2-oxoethyl]4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (300 mg, 0.76 mmol) in ethanol (4 ml) was treated dropwise with pyrrolidine (0.63 ml, 7.60 mmol) and the resulting solution was heated at 60° C. for 9 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (4:1) to afford the title compound as a pale yellow oil (360 mg).
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]([F:19])=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16].CC(C)([O-])C.[K+]>CS(C)=O.CCOC(C)=O>[Cl:9][C:10]1[C:11]([O:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]2)=[CH:12][C:13]([F:19])=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16]
Reactant: OCC1CC=CCC1
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(Cl)c(OCC2CC=CCC2)cc1F
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
To a solution of cyclohex-3-en-1-ylmethanol (1.00 g) and 5-chloro-2,4-difluoro-benzoic acid (1.72 g) in DMSO (36 mL) at 14° C. (bath) was added potassium tert-butoxide (2.20 g) gradually. The mixture was stirred at that temp for 5 min then at rt for 30 min. Diluted with EtOAc, the contents were washed with 1:4 mixture of 1M HCl and 1M NaH2PO4 (3×) and brine, and dried (Na2SO4). After filtration and concentration, the product was obtained as white solid (2.48 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[F:12][C:13]([F:21])([F:20])[C:14]1([C:17](O)=[O:18])[CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:11][C:3]1[C:2]([NH2:1])=[C:9]([Cl:10])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:17]([C:14]1([C:13]([F:21])([F:20])[F:12])[CH2:16][CH2:15]1)=[O:18]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: NCc1ccc(Cl)c(N)c1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Nc1c(Cl)ccc(CNC(=O)C2(C(F)(F)F)CC2)c1Cl

Procedure:
The sub-title compound is prepared from 3-amino-2,4-dichloro-benzylamine (0.310 g, 1.01 mmol), 1-trifluoromethyl-cyclopropane carboxylic acid (0.17 g, 1.1 mmol), TBTU (0.39 g, 1.2 mmol) and TEA (0.71 mL) in DMF in analogy to example 3e.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[NH:6][CH:5]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Fc1cccc2[nH]ccc12
Solvent: CCO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cccc(F)c23)CC1
Yield: 26.3 %

Procedure:
A stirred solution of 4-fluoroindole (400 mg, 3.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (650 mg, 3.3 mmol), and pyrrolidine (0.62 mL, 7.4 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue subjected to chromatography on silica gel with 20% ethyl acetate/hexanes to afford a yellow solid (250 mg, 27%).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([NH:42][CH:43]1[CH2:48][C:47]([CH3:50])([CH3:49])[N:46]([CH3:51])[C:45]([CH3:53])([CH3:52])[CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][NH:42][CH:43]2[CH2:48][C:47]([CH3:50])([CH3:49])[N:46]([CH3:51])[C:45]([CH3:53])([CH3:52])[CH2:44]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN1C(C)(C)CC(NC(=O)CCl)CC1(C)C
Product: CCN(Cc1ccc(OCCNC2CC(C)(C)N(C)C(C)(C)C2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 14 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)acetamide (23 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (4.2 mg) was obtained.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][CH:22]=[CH:23][N:24]=3)=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.Br[CH:28]([CH2:33][CH3:34])[C:29]([O:31]C)=[O:30]>>[ClH:1].[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:12]2[CH:25]=[CH:26][C:9]([O:8][CH2:7][C@@H:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH2:34][CH2:33][CH2:28][C:29]([OH:31])=[O:30])=[CH:10][CH:11]=2)=[CH:15][CH:16]=1
Reactant: CCC(Br)C(=O)OC
Reactant: c1csc(-c2ccc(Cc3ccc(OC[C@@H]4CCCN4)cc3)cc2)n1
Agent: Cl
Product: O=C(O)CCCN1CCC[C@H]1COc1ccc(Cc2ccc(-c3nccs3)cc2)cc1
Yield: 42.3 %

Procedure:
The title compound (56 mg, 42%) was prepared from the product of Example 150 (0.1 g, 0.28 mmol) and methyl bromobutyrate (0.062 g, 0.34 mmol) using the procedure of Example 147; 1HNMR (400 MHz, CD3OD) δ 8.07 (m, 1H), 7.90 (d, J=8 Hz, 1H), 7.85 (m, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 4.32 (m, 1H), 4.20 (m, 1H), 4.10 (m, 1H), 4.04 (s, 2H), 3.95 (m, 1H), 3.65 (m, 3H), 3.36 (m, 2H), 2.50-2.00 (m, 6H); MS.?
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:16]2[C@@H:17]3[C@@H:22]([C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[CH2:19][CH2:18]3)[CH2:13][CH2:14][CH2:15]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)ccc1N
Yield: 64 %

Procedure:
The title compound is prepared from 4-amino-3-methoxy-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 64% of theory; LC (method 4): tR=1.84 min; Mass spectrum (ESI+): m/z=337 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:11]1[CH2:10][CH:9]([NH:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)[CH2:12]1
Reactant: Cc1ccnc(NC2CN(C(=O)OC(C)(C)C)C2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccnc(NC2CNC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 3-[(4-methyl-2-pyridyl)amino]azetidine-1-carboxylate (120 mg, 0.456 mmol) was dissolved in DCM (10 ml) under nitrogen. Trifluoroacetic acid (0.843 ml, 11.4 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, the residue was dissolved in methanol and passed through a SCX column. The product was eluted by 2M ammonia in methanol, the solution was evaporated to dryness and the residue was used directly in the next step. MS (ESI) m/z=164.1 [M+1]+.
Reaction SMILES: [C:1]1([P:7]([CH2:14]S)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([NH:19][CH2:20][C:21](O)=[O:22])(=[O:18])[CH3:17].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:19]([C:16]([CH3:17])=[O:18])[CH2:20][C:21]([CH2:14][P:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:22]
Reactant: SCP(c1ccccc1)c1ccccc1
Reactant: CC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(=O)NCC(=O)CP(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
Phosphinothiol 20 (100 mg, 0.43 mmol) and N-acetylglycine (55 mg, 0.47 mmol) were dissolved in DMF (3 mL) under Ar(g). DCC (98 mg, 0.47 mmol) was added, and the mixture was stirred for 12 h at room temperature. The DCU by-product was removed by filtration, solvent was removed under reduced pressure, and the residue was purified by chromatography as in Method A. AcGlyCH2PPh2 was isolated as a white solid in 67% yield. Spectral data. 1H NMR (CDCl3, 300 MHz) δ 7.46-7.39 (m, 4 H), 7.38-7.36 (m, 6 H), 6.44 (bs, 1 H), 4.15 (d, J=5/7 Hz, 2 H), 3.53 (d, J=3.6 Hz, 2 H), 2.02 (s, 3 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 196.13, 170.29, 136.45 (d, J=13.6 HZ), 132.62 (d, J=19.1 Hz), 129.17, 128.54 (d, J=6.7 Hz), 48.98, 25.29 (d, J-24.2 Hz), 22.84 ppm; 31P NMR (CDCl3, 121 MHz) δ −15.20 ppm; MS (ESI) m/z 331.08 (MH+—332.2, MK+—370.0).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]([O:15][CH2:16][C@@H:17]3[CH2:20][CH2:19][N:18]3[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:12]=[N:13][CH:14]=2)=[CH:3][CH:2]=1>CO.[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([O:15][CH2:16][C@@H:17]3[CH2:20][CH2:19][N:18]3[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:12]=[N:13][CH:14]=2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(C=Cc2ccncc2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 81.7 %

Procedure:
To a solution of 5-(2-(4-pyridinyl)ethenyl)-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 59a (188 mg, 0.51 mmol) in MeOH (10 mL) was added Pd/C (20 mg), and the mixture was stirred at room temperature for 40 hours. The catalyst was filtered off, and the solvent was removed under vacuum. The residue was chromatographed on a silica gel column, eluting with CH2Cl2:MeOH 10:2 to 10:5 to afford the title compound (154 mg). MS (CI/NH3) m/z 370 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.32 (m, 2H), 3.89 (m, 2H), 4.10 (m, 1H), 4.28 (m, 1H), 4.50 (m, 1H), 7.02 (m, 1H), 7.02 (m, 1H), 7.08 (m, 2H), 8.06 (m, 1H), 8.20 (m, 1H), 8.51 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][S:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>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.O>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH:28]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Clc1nc(N2CCOCC2)c2ccc(Br)cc2n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a 50 mL round bottom flask, 7-bromo-2-chloro-4-morpholin-4-yl-quinazoline (0.65 g, 0.0019 mol), 3-methylsulfonylphenylboronic acid (0.35 g, 0.0018 mol), sodium carbonate (0.314 g, 0.0029 mol), DMF (25 mL) and water (6 mL) were added and degassed the reaction vessel with nitrogen for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (0.069 g, 0.00099 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified; using column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to yield the desired product [400 mg, 80%]. LC-MS (ESI): Calculated mass: 403.1; Observed mass: 404.0 [M+H]+ (RT: 1.36 min).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:38][Si:39]([C:42]#[CH:43])([CH3:41])[CH3:40]>CN(C=O)C.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)I>[CH3:11][C:5]1[CH:4]=[CH:3][C:2]([C:43]#[C:42][Si:39]([CH3:41])([CH3:40])[CH3:38])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(Br)cc1C(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C#C[Si](C)(C)C)cc1C(N)=O
Temperature: 120 °C

Procedure:
To a mixture of 5-bromo-2-methylbenzamide (I69) (0.292 g, 1.36 mmol), PdCl2(PPh3)2 (0.049 g, 0.070 mmol), triphenylphosphine (0.054 g, 0.21 mmol) and copper iodide (0.036 g, 0.19 mmol) in DMF (3 mL) was added triethylamine (0.570 mL, 4.09 mmol) and trimethylsilylacetylene (0.210 mL, 1.49 mmol) and the resulting mixture heated under microwave irradiation at 120° C. for 25 minutes. The resulting mixture was concentrated under reduced pressure and purified using silica gel column chromatography (0-20% EtOAc/petroleum benzine 40-60° C.) to give the title compound (I70) (0.190 g, 60%); 1H NMR (400 MHz, d6-DMSO) δ 7.80 (s, 1H), 7.40 (m, 3H), 7.24 (d, J=7.9 Hz, 1H), 2.36 (s, 3H), 0.22 (s, 9H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]>>[CH2:13]([O:12][C:10](=[O:11])[C:9]([C:7]#[N:8])=[CH:1][CH2:2][CH:3]([CH3:5])[CH3:4])[CH3:14]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)CC=O
Product: CCOC(=O)C(C#N)=CCC(C)C

Procedure:
Condensing isovaleraldehyde with ethyl cyanoacetate to form 2-cyano-5-methylhex-2-enoic acid ethyl ester;
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:25])=[C:6]([C@@H:14]2[CH2:18][CH2:17][N:16]([CH3:19])[C@H:15]2[CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:7]([O:12][CH3:13])=[CH:8][C:9]=1[O:10][CH3:11])(=[O:3])[CH3:2].[Cl:26][C:27]1[C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:22]([O:21][CH2:20][C@H:15]1[C@H:14]([C:6]2[C:7]([O:12][CH3:13])=[CH:8][C:9]([O:10][CH3:11])=[C:4]([C:1](=[O:3])[CH3:2])[C:5]=2[O:25][C:33](=[O:34])[C:32]2[CH:31]=[CH:30][CH:29]=[N:28][C:27]=2[Cl:26])[CH2:18][CH2:17][N:16]1[CH3:19])(=[O:24])[CH3:23]
Reactant: O=C(O)c1cccnc1Cl
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2COC(C)=O)c(O)c1C(C)=O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2COC(C)=O)c(OC(=O)c2cccnc2Cl)c1C(C)=O

Procedure:
(+/−)-trans-Acetic acid 3-(3-acetyl-2-hydroxy-4,6-dimethoxy-phenyl)-1-methyl-pyrrolidin-2-ylmethyl ester (1.65 g, 4.7 mmol) was reacted with 2-chloro-pyridine-3-carboxylic acid (2.44 g, 15.49 mmol) in the presence of dry pyridine (25 mL) and POCl3 (2.1 mL, 23.43 mmol) using the conditions described in example 52 to get trans-2-Chloro-nicotinic acid 2-(2-acetoxymethyl-1-methyl-pyrrolidin-3-yl)-6-acetyl-3,5-dimethoxy-phenyl ester. This was converted in situ to the title compound(66) using NaH (1.29 g, 26.86 mmol) in 1,4-dioxane (25 mL) as described in example 26.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:11]=1[CH2:12][O:13][CH2:14][C:15]#[C:16][CH2:17]Br>O1CCCC1>[CH2:1]([NH:8][CH2:17][C:16]#[C:15][CH2:14][O:13][CH2:12][C:11]1[CH:19]=[C:20]([Br:23])[CH:21]=[CH:22][C:10]=1[F:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1COCC#CCBr
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: Fc1ccc(Br)cc1COCC#CCNCc1ccccc1
Yield: 61.8 %

Procedure:
A solution of benzylamine (0.98 ml, 8.93 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl bromide (300 mg, 0.893 mmol) in tetrahydrofuran (4.5 ml). The cloudy reaction mixture was stirred for about twenty hours, at which time no starting material remained, as determined by thin layer chromatography. The solvents were removed in vacuo. The residue was taken up in methylene chloride and washed with 1 M potassium carbonate. The aqueous phase was back extracted with methylene chloride (2×15 ml). The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The resulting oil was further purified by flash chromatography, affording 200 mg (62%) of the title intermediate.