Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH:33]=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:28][CH2:29][CH:30]([CH2:33][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH3:13])[CH2:31][CH2:32]1)=[O:26])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)CC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Reaction between (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amine (described above) and 4-formyl-piperidine-1-carboxylic acid tert-butyl ester using standard reductive amination conditions yielded 4-{[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester, which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A, followed by treatment with HCl to cleave the BOC group to yield 320. 400 MHz 1H NMR CDCl3: 9.21 (s, 2H); 7.18 (s, 1H); 5.18 (brs, NH2); 3.96 (t, 4H, J=4.7 HZ); 3.81 (t, 4H, J=4.7 Hz); 3.71 (s, 2H, CH2); 3.01 (d, 2H, J=12.2 Hz); 2.56-1.50 (m, 2H); 2.23 (m, 5H, CH2&Me); 1.73 (d, 2H, J=12.8 Hz); 1.65-1.50 (m, 1H); 1.07-0.97 (m, 2H). LC-MS (m+1)=455.34
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][S:4][C:3]1=[S:8].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[C:17]=1[OH:18])[CH:13]=O.N1CCCCC1>C(O)(=O)C>[OH:9][C:10]1[CH:11]=[C:12]([CH:13]=[C:5]2[S:4][C:3](=[S:8])[N:2]([CH3:1])[C:6]2=[O:7])[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[C:17]=1[OH:18]
Reactant: CN1C(=O)CSC1=S
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CN1C(=O)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)SC1=S
Temperature: 100 °C

Procedure:
A solution containing 0.74 g (0.005 mol) of 3-methyl-2-thioxothiazolidin-4-one, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde, 0.05 ml of piperidine in 10 ml of acetic acid was heated for 8 h at 100° C. The product was filtered and washed with 2-propanol. Yield 0.87 g (56%), mp 274-276° C.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:15].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]1[O:15][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](O)C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
A mixture of trans-tert-butyl 4-fluoro-3-hydroxypiperidine-1-carboxylate (3.10 g, 14.1 mmol) and 4-methylbenzene-1-sulfonyl chloride (5.39 g, 28.3 mmol) in pyridine (20 mL) was stirred at room temperature for 18 hours. The pyridine was removed in vacuo, and the residue was dissolved in ethyl acetate (30 mL), washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (hexane:ethyl acetate 2:1) to give trans-tert-butyl 4-fluoro-3-(tosyloxy)piperidine-1-carboxylate (3.95 g, 75%) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[CH2:10][C@@H:11]([NH2:26])[C:12]([NH:14][C@H:15]([C:20](=[O:25])[N:21]([O:23][CH3:24])[CH3:22])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:33]=[CH:32][C:31]([CH:34]2[CH2:38][CH:37](OC)O[CH:35]2OC)=[CH:30][CH:29]=1.FC(F)(F)C(O)=O>ClCCCl>[CH2:1]([O:8][C:9](=[O:27])[CH2:10][C@@H:11]([N:26]1[CH:37]=[CH:38][C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:29][CH:30]=2)=[CH:35]1)[C:12]([NH:14][C@H:15]([C:20](=[O:25])[N:21]([O:23][CH3:24])[CH3:22])[CH2:16][CH:17]([CH3:18])[CH3:19])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CC(=O)OCc1ccccc1
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Yield: 48 %

Procedure:
As described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo-[9.6.1.012,17 ]-octadeca-11(18),12,14,16-tetraen-9-yl)-3-(3-phenyl-1H-pyrrol-1-yl acid benzyl ester, 3(R)-amino-N-(1(S)-(N-methoxy-N-methylcarbamoyl)-3-methylbutyl)succinamic acid benzyl ester was deprotected. The crude amine salt and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) were condensed in anhydrous 1,2-dichloroethane with trifluoroacetic acid to provide in 48% yield 3(R)-(3-biphenyl-4-yl-1H-pyrrol-1-yl)-N-[1(S)-(N-methoxy-N-methylcarbamoyl)-3-methyl-butyl]succinamic acid benzyl ester as an amorphous solid. 1H NMR (CDCl3): δ 7.62 (d, 2H, J=7.4 Hz), 7.58 (s, 3H), 7.44 (t, 2H, J=7.7 Hz), 7.35-7.21 (m, 7H), 7.10 (s, 1H), 6.80 (t, 1H, J=2.2 Hz), 6.60 (bs, 1H), 5.17-1.13 (m, 1H), 5.10 (s, 2H), 4.97-4.92 (m, 1H), 3.77 (s, 3H), 3.44 (dd, 1H, J=5.7, 17.1 Hz), 3.17 (s, 3H), 3.03 (dd, 1H, J=8.8, 16.5 Hz), 1.67-1.36 (m, 3H), 0.92 (d, 3H, J=6.25 Hz), 0.87 (d, 3H, J=6.3 Hz). Anal. Calculated for C35H39N3O5 : C, 72.27; H, 6.76; N, 7.22. Found: C, 72.19; H, 6.78; N, 7.16.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH:35]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]>>[CH3:31][C:30]1[CH:29]=[CH:28][C:27]([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:37]=[C:36]([N:44]3[CH2:45][CH2:46][O:47][CH2:48][CH2:49]3)[CH:35]=2)=[CH:26][C:25]=1[NH:24][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)CC1
Reactant: Cc1ccc(NC(=O)c2cc(N3CCOCC3)cc(C(F)(F)F)c2)cc1N
Product: Cc1ccc(NC(=O)c2cc(N3CCOCC3)cc(C(F)(F)F)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 77 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 50, 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-morpholino-5-trifluoromethylbenzamide to give N-[2-methyl-5-(3-morpholino-5-trifluoromethylbenzamido)phenyl]-3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzamide in 77% yield; NMR Spectrum: (DMSOd6) 1.37 (s, 9H), 1.55 (m, 2H), 1.95 (m, 2H), 2.19 (s, 3H), 3.2 (m, 2H), 3.25 (t, 4H), 3.63 (m, 2H), 3.77 (t, 4H), 4.63 (m, 1H), 7.18 (m, 1H), 7.22 (d, 1H), 7.37 (s, 1H), 7.41 (t, 1H), 7.5 (s, 2H), 7.57 (m, 1H), 7.62 (s, 1H), 7.7 (s, 1H), 7.78 (d, 1H), 9.83 (s, 1H), 10.31 (s, 1H); Mass Spectrum: M+H+ 683.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH:31]1[CH2:39][OH:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:40][CH2:39][CH:31]1[CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]1[C:26]([C:22]1[N:23]=[CH:24][N:25]=[C:20]([N:17]2[CH2:16][CH2:15][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:19][CH2:18]2)[CH:21]=1)=[O:27]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: OCC1Cc2ccccc2N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4c5ccccc5CC4CO)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.25 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 45 mg (0.30 mmol) (2,3-dihydro-1H-indole-2-yl)-methanol in 50 μL (0.36 mmol) TEA and 0.90 mL DMF were combined with 85 mg (0.27 mmol) TBTU and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and partially evaporated down. The precipitate formed was suction filtered and dried.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[SH:14].[C:15]1([CH3:31])[CH:20]=[CH:19][C:18]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:17][CH:16]=1.[OH-].[Na+].O>CN(C=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[S:14][CH2:31][C:15]1[CH:16]=[CH:17][C:18]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH3:27])=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:20]=1
Reactant: Cc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)c2ccc(CSc3nc4cccc(C)c4c(=O)n3C)cc2)cc1
Yield: 35.4 %

Procedure:
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (197 mg), 4-(4-toluoyl)benzyl bromide (336 mg) and 1N-sodium hydroxide/water (1 ml) in DMF (10 ml) was stirred at room temperature for 30 minutes. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate: chloroform=5:1:1) and crystallized from methanol to provide the title compound as colorless solid (140 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C@:11]1([CH3:26])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C@:11]1([CH3:26])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[S:36]
Reactant: C[C@@]1(C(=O)Nc2ccccc2Br)CCCN1C(=O)OCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: C[C@@]1(C(=S)Nc2ccccc2Br)CCCN1C(=O)OCc1ccccc1

Procedure:
To a solution of EXAMPLE 5B (1.25 g) in toluene (12 mL) was added Lawesson's reagent (1.212 g) and the mixture heated at reflux for 5 hours. After cooling, the solid was filtered and the filtrate concentrated. The residue was dissolved in ethyl acetate and the solution washed with 5% aqueous citric acid and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated, and the residue purified by flash chromatography on silica gel using 4:6 to 6:4 dichloromethane/hexane to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:15])[N:5]([CH3:14])[CH:6]=[CH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1C(=O)N([I:23])C(=O)C1>CN(C=O)C.C(Cl)Cl>[I:23][C:6]1[N:5]([CH3:14])[C:4](=[O:15])[C:3]([O:2][CH3:1])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1
Reactant: CCOC(=O)c1ccn(C)c(=O)c1OC
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(I)n(C)c(=O)c1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.3 %

Procedure:
To a solution of Intermediate 1 (101 mg, 0.478 mmol) in DMF (0.5 mL) was added NIS (108 mg, 0.478 mmol) at rt. The reaction was stirred at rt for 3 days. An additional equivalent of NIS (67 mg, 0.30 mmol) was added and the reaction mixture heated at 60° C. overnight. The reaction was allowed to cool, diluted with DCM (40 mL) and the organic portion washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in a small amount of DCM and charged to a 12 g silica gel cartridge which was eluted with a 25 min gradient from 0-100% EtOAc/hexane to give Intermediate 19A (81 mg, 50% yield) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4].[OH2:13]>C(#N)C>[OH:13][CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: O
Solvent: CC#N
Product: N#Cc1ccc(C(=O)CO)cc1

Procedure:
A solution of 1 g of 4-(2-bromoacetyl)benzonitrile in acetonitrile (5 mL) and water (10 mL) is treated under microwave irradiation (125° C., 50 min). The same experiment is conducted five times. All the vials are collected, extracted with ethyl ether, dried over magnesium sulfate and concentrated under vacuum to give the desired compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:22]([NH:24][CH3:25])=[O:23]>>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][C@H:21]([NH:20][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([S:10]([CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12])[N:8]=1)=[O:19])[C:22](=[O:23])[NH:24][CH3:25]
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Reactant: CC(C)CS(=O)(=O)c1nc(C(=O)O)ccc1C1CC1
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1ccc(C2CC2)c(S(=O)(=O)CC(C)C)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 351 b) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials. MS (EI): m/e=424.6 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[NH:19][C:18]5[N:26]=[CH:27][CH:28]=[CH:29][C:17]=5[N:16]4[C:30]=3[C:31]3[CH:36]=[CH:35][C:34]([C:37]4([NH:41]C(=O)OC(C)(C)C)[CH2:40][CH2:39][CH2:38]4)=[CH:33][CH:32]=3)=[CH:9][CH:8]=2)=[O:5])[CH2:3][CH2:2]1.[ClH:49].O1CCOCC1>C(Cl)Cl>[ClH:49].[ClH:49].[ClH:49].[NH2:41][C:37]1([C:34]2[CH:33]=[CH:32][C:31]([C:30]3[N:16]4[C:17]5[CH:29]=[CH:28][CH:27]=[N:26][C:18]=5[NH:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[C:15]4=[N:14][C:13]=3[C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])=[CH:12][CH:11]=3)=[CH:36][CH:35]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(NC(=O)C5CC5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(-c4ccc(NC(=O)C5CC5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 78.1 %

Procedure:
tert-Butyl {1-[4-(2-{4-[(cyclopropylcarbonyl)amino]phenyl}-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (53.9 mg, 0.0965 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 19 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (48.8 mg, 78.1%) as yellow solid. 1HNMR (DMSO-d6) 500 MHz δ: 10.36 (s, 1H), 8.71-8.63 (m, 3H), 8.13-8.10 (m, 1H), 7.97-7.93 (m, 1H), 7.58-7.52 (m, 4H), 7.43-7.37 (m, 3H), 7.34-7.29 (m, 3H), 7.17-7.12 (m, 1H), 6.92-6.88 (m, 1H), 6.75 (dd, J=8.3, 4.9 Hz, 1H), 2.63-2.40 (m, 4H), 2.25-2.12 (m, 1H), 1.86-1.76 (m, 2H), 0.81-0.75 (m, 4H); LCMS: 539 [M+H].
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH:3]([OH:6])[C:4]#[CH:5].[H-].[Na+].[CH2:10](Br)[CH:11]=[CH2:12]>CN(C=O)C.CCOCC>[CH2:12]([O:6][CH:3]([CH:2]([CH3:7])[CH3:1])[C:4]#[CH:5])[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: C#CC(O)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CC(OCC=C)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.9 %

Procedure:
A solution of 4-methylpent-1-yn-3-ol (2.00 g, 20.38 mmol) in DMF (30 ml) was cooled (0° C. ice bath) and treated with 60% NaH (0.992 g, 24.80 mmol). The reaction was stirred for 20 min, then warmed to room temperature and stirred for 1 hr. To this was added allyl bromide (5.3 ml, 61.2 mmol) over 5 min. The reaction was stirred over the weekend. The reaction was diluted with Et2O (100 mL), washed with water (4×25 mL), brine (25 mL), dried (MgSO4), filtered and concentrated to give the product, 3-(allyloxy)-4-methylpent-1-yne (2.401 g, 13.03 mmol, 63.9% yield) as a pale yellow mobile oil. 1H NMR consistent with expected product; contains approx 4:1 product/SM. Used as-is without further purification. 1H NMR (CDCl3) δ: 5.86-5.99 (m, 1H), 5.32 (dq, J=17.2, 1.7 Hz, 1H), 5.16-5.25 (m, 1H), 4.28 (ddt, J=12.7, 5.0, 1.6 Hz, 1H), 4.19 (td, J=5.7, 2.1 Hz, 1H), 3.98 (ddt, J=12.7, 6.3, 1.3 Hz, 1H), 3.87 (dd, J=5.8, 2.0 Hz, 1H), 2.41 (d, J=2.0 Hz, 1H), 1.92-2.03 (m, 1H), 0.98-1.06 (m, 8H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[CH:8][CH2:7]1)=[O:5])C.[OH-].[K+]>O.C(O)C>[F:27][C:16]([F:28])([C:17]([F:25])([F:26])[C:18]([F:23])([F:24])[C:19]([F:22])([F:20])[F:21])[CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH:8]=1
Reactant: CCOC(=O)C1CC=C(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CC=C(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution 4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyl)-cyclohex-3-enecarboxylic acid ethyl ester (41) (1 equi.) and potasium hydroxide (3.5 equi.) in water-ethanol (1:1) (25 mL/mmole) was stirred at 80 C temperature for 2 h., cooled to room temperature and quenched with hydrochloric acid (5%), filtered resulted white solid, washed with water and dried under vacuum to give 4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyl)-cyclohex-3-enecarboxylic acid (42) as a white solid (93%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][C:6]([NH:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=[O:7].[Si](C=[N+]=[N-])(C)(C)[CH3:20]>C(Cl)Cl.CO>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][C:6]([NH:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O:13][CH3:20])=[O:12])=[O:7]
Reactant: COC(=O)CCC(=O)Nc1ncccc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCC(=O)Nc1ncccc1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 107.2 %

Procedure:
2-(4-Methoxy-4-oxobutanamido)nicotinic acid (ii-h-1) (1.28 g, 4.8 mmol) was dissolved in an equimolar mixture of CH2Cl2 and methanol (20 mL) and cooled to 0° C. TMS diazomethane (2M solution in diethyl ether; 5.2 mL, 10.6 mmol) was added dropwise. The mixture was stirred for 1 h and warmed to 23° C. Volatiles were removed under reduced pressure to provide ii-h as a pale yellow solid (1.37 g, 100%) MS m/z=267 (M+1).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:22](=[O:23])[NH:21][CH:20](SC)[NH:19][C:18]2=[O:26])=[CH:13][CH:12]=1>O>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:18](=[O:26])[NH:19][CH:20]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])[NH:21][C:22]2=[O:23])=[CH:15][CH:16]=1
Reactant: CSC1NC(=O)N(c2ccc(C)cc2)C(=O)N1
Reactant: CC(C)CN
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(N2C(=O)NC(NCC(C)C)NC2=O)cc1
Reaction time: 5 h
Yield: 89.5 %

Procedure:
Isobutylamine (1.60 g.) was added to acetic acid (1.20 g.) at 20°-25° C. during 15 minutes. 3-(4-Methylphenyl)-6-methylthiotetrahydro-1,3,5-triazine-2,4-dione (4.98 g.) was then added, and the whole mixture stirred at 120°-125° C. for 5 hours and then cooled. Water (50 ml.) was added and the mixture stirred thoroughly. The solid produced was collected by filtration, washed with water and dried to give 3-(4-methylphenyl)-6-isobutylaminotetrahydro-1,3,5-triazine-2,4-dione (4.90 g., 89%), m.p. 297°-301° C.
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([C:7]1[NH:8][C:9]([S:12][CH2:13][CH2:14][CH3:15])=[CH:10][CH:11]=1)=[O:6])C.[OH-].[Na+].Cl>O>[CH2:13]([S:12][C:9]1[NH:8][C:7]([C:5](=[O:6])[C:4]([OH:16])=[O:3])=[CH:11][CH:10]=1)[CH2:14][CH3:15]
Reactant: CCCSc1ccc(C(=O)C(=O)OCC)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCSc1ccc(C(=O)C(=O)O)[nH]1
Yield: 33 %

Procedure:
A mixture of 5-n-propylthio-2-pyrrolylglyoxylic acid ethyl ester (2.4 g.) and sodium hydroxide (1.0 g.) in water (100 ml.) was heated on a steam bath for 3 hours. The solution was cooled, acidified to pH 1 with dilute hydrochloric acid and the product extracted with chloroform. Evaporation of the solvent and recrystallization from petroleum ether (B.P. 40°-60°) gave 5-n-propylthio-2-pyrrolylglyoxylic acid (0.7 g.) as yellow crystals, M.P. 87°. Found: C, 50.34; H, 5.21; N, 6.54. C9H11NO3S requires: C, 50.68; H, 5.20; N, 6.57%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]2[NH:17][C:18]3[CH:24]=[C:23]([C:25]([O:27]CC)=[O:26])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].O1CCOCC1.[OH-].[Na+].Cl>O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]2[NH:17][C:18]3[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: CCCc1c(SCCCCSc2nc3ccc(C(=O)OCC)cc3[nH]2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCc1c(SCCCCSc2nc3ccc(C(=O)O)cc3[nH]2)ccc(C(C)=O)c1O
Temperature: 60 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
A mixture of ethyl 2-[4-(4-acetyl-3-hydroxy-2-propylphenylthio)butylthio]benzimidazole-5-carboxylate (2.50 g), 1,4-dioxane (30 ml) and sodium hydroxide (1.03 g) in water (30 ml) was stirred at 60 ° C. for 2 hours. This mixture was poured into ice-water, made acidic with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography, eluting with dichloromethane-methanol (10:1), to give the title compound (1.52 g, 64.5 %) as yellow crystals, mp 90-95° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]1[O:10][C:9](/[CH:15]=[CH:16]/[CH:17]2[CH2:19][CH2:18]2)([C:11]([F:14])([F:13])[F:12])[C:8]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:7]=2[N:6](CC2C=CC(OC)=CC=2)[C:5]1=[O:34].O>C(#N)C>[Br:1][CH2:2][CH2:3][C@@H:4]1[O:10][C@:9](/[CH:15]=[CH:16]/[CH:17]2[CH2:18][CH2:19]2)([C:11]([F:13])([F:14])[F:12])[C:8]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:7]=2[NH:6][C:5]1=[O:34]
Reactant: COc1ccc(CN2C(=O)C(CCBr)OC(/C=C/C3CC3)(C(F)(F)F)c3cc(Cl)ccc32)cc1
Solvent: O
Solvent: CC#N
Product: O=C1Nc2ccc(Cl)cc2[C@@](/C=C/C2CC2)(C(F)(F)F)O[C@H]1CCBr
Reaction time: 0.33 h

Procedure:
To a room temperature solution of 750 mg of trans-3-(2-bromoethyl)-7-chloro-5-cyclopropylethenyl-1,5-dihydro-1-(4-methoxybenzyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 35 mL of acetonitrile was added 18 mL of water and 3.78 g of ceric ammonium nitrate. After 20 min, the reaction mixture was partitioned between eater and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. This produced two diastereomeric products which were separated by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes). The first diastereomer eluted (162 mg) was the title compound.