Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([C:14]3=[CH:15][C:16]4[S:20][CH:19]=[N:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:3]1=[O:22].[CH3:23]C1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Cl.[Cl:46][C:47]1[N:51]([CH3:52])[C:50](CCl)=[N:49][CH:48]=1.BrCC1OC(C(F)(F)F)=CC=1>>[Cl:46][C:47]1[N:51]([CH3:52])[C:50]([CH2:1][N:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]3([C:14]4=[CH:15][C:16]5[S:20][C:19]([CH3:23])=[N:18][C:17]=5[CH:21]=[C:13]4[O:12][CH2:11]3)[C:3]2=[O:22])=[N:49][CH:48]=1
Reactant: Cn1c(Cl)cnc1CCl
Reactant: CN1C(=O)C2(COc3cc4ncsc4cc32)c2ccccc21
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: Cl
Agent: FC(F)(F)c1ccc(CBr)o1
Product: Cc1nc2cc3c(cc2s1)C1(CO3)C(=O)N(Cc2ncc(Cl)n2C)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 5-chloro-2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one was obtained (68%) as a colorless solid: mp 177-178° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ7.63 (dd, J=8.6, 1.1 Hz, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.29-7.23 (m, 1H), 7.08-6.92 (m, 4H), 5.42 (d, J=15.4 Hz, 1H), 5.08-5.00 (m, 1H), 4.85-4.74 (m, 2H), 3.67 (s, 3H), 2.51 (s, 3H); 13C NMR (75 MHz, CDCl3) δ176.8, 169.6, 160.5, 149.1, 142.1, 141.8, 132.1, 129.1, 124.6, 123.7, 123.3, 122.5, 119.6, 119.3, 110.7, 108.7, 81.3, 60.5, 58.2, 38.4, 31.2, 20.2; MS (ES+) m/z 437.0 (M+1), 439.0 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[CH2:12][NH2:13].C(N(C(C)C)CC)(C)C>ClCCl.C(OCC)C>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[CH2:12][NH:13][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: NCc1cc(Br)ccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)NCc1cc(Br)ccc1F
Reaction time: 3 h
Yield: 95.7 %

Procedure:
Add acetyl chloride (0.18 mL, 2.49 mmol) to a mixture of 5-bromo-2-fluorobenzylamine hydrochloride (500 mg, 2.08 mmol) in dichloromethane (8 mL) and diisopropylethylamine (0.90 mL, 5.20 mmol) and stir 3 h. Dilute with diethyl ether and separate the layers. Wash the organic layer twice with 1 N hydrochloric acid and once with an aqueous saturated solution of sodium chloride. Dry (sodium sulfate), filter, and concentrate to give the title compound as a white crystalline solid (490 mg, 96%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([C:19](=[O:29])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=O)[NH2:27])[CH:21]=2)[C:12]=1[F:30])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(OCC)=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([C:19](=[O:29])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=2)[C:12]=1[F:30])[CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(OC)c(C(=O)c2cccc(C(N)=O)c2)c1F
Agent: CCOP(=O)(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(OC)c(C(=O)c2cccc(C#N)c2)c1F
Reaction time: 24 h

Procedure:
Step 4 A mixture of {(R)-1-[3-(3-carbamoyl-benzoyl)-2-fluoro-4-methoxy-phenyl]-propyl}-carbamic acid tert-butyl ester (269 mg, 0.62 mmol) from Step 3, ethyl dichlorophosphate (0.14 mL, 1.25 mmol, 2 eq.) and DBU (0.28 mL, 1.87 mmol, 3 eq.) in DCM (3 mL) was stirred for 24 hours. The mixture was then diluted with DCM (15 mL) and water (15 mL) and the organic phase was washed with brine, isolated by phase separation and concentrated to give crude {(R)-1-[3-(3-cyano-benzoyl)-2-fluoro-4-methoxy-phenyl]-propyl}-carbamic acid tert-butyl ester which was used in the next step. [M−H]− 411
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9]Br)[CH:3]=1.[C-:11]#[N:12].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH2:9][C:11]#[N:12]
Reactant: Cc1cc(Br)cc(CBr)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Product: Cc1cc(Br)cc(CC#N)c1
Temperature: 25 °C
Yield: 39.5 %

Procedure:
To a stirred solution of 1-bromo-3-(bromomethyl)-5-methylbenzene (6.56 kg, 0.1515 M) in ethanol (20 L) were added potassium cyanide (2.38 kg, 36.55 mol) and distilled water (10 L) in this order. The mixture was refluxed for 3 hours. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate (30 L) and brine (20 L). The organic layer was dried with magnesium sulfate (2 kg) and concentrated under reduced pressure to give a brown-colored oil. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate/hexane, 1:9) to afford 3-bromo-5-methylbenzyl cyanide (2.06 kg, 9.81 mol, 39%) as a pale brown oil.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8](Cl)=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].Cl.[NH2:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[OH:22].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[OH:22])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COc1ccc2nc(Cl)sc2c1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1Br
Temperature: 125 °C
Reaction time: 12 h

Procedure:
To the solution of 7-bromo-2-chloro-6-methoxybenzo[d]thiazole (150 mg, 0.539 mmol, 1.0 eq) in 1 mL of NMP was added (1R,2R)-2-aminocyclohexanol hydrochloride (0.123 mg, 0.809 mmol, 1.5 eq) and DIPEA (263 μL, 1.503 mmol, 2.8 eq) at room temperature. The reaction mixture was stirred at 125° C. for 12 hours, thereafter the mixture was diluted with saturated sodium bicarbonate solution (ca. 100 mL) and aqueous layer extracted with ethyl acetate (ca. 200 mL×3). Combined organic layers were dried over sodium sulfate, filtered and condensed under reduced pressure to give crude product as brown oil which was sufficiently pure and was carried to next step without further purification. LC/MS (m/z) [359.0] (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([OH:14])[NH:11][N:10]=1.[OH-].[Na+].Cl[CH:18]([F:20])[F:19]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([O:14][CH:18]([F:20])[F:19])[NH:11][N:10]=1
Reactant: FC(F)Cl
Reactant: Oc1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)Oc1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Reaction time: 6 h
Yield: 47.3 %

Procedure:
237 g of 3-(2,4-dichlorophenyl)-5-hydroxy-1H-pyrazol from Example 3.1 were initially charged in 2160 ml of dioxane. A solution of 84 g of sodium hydroxide in 250 ml of water was added, and the mixture was heated at reflux. With stirring, 620 g (7.17 mol, 6.9 eq.) of gaseous chlorodifluoromethane were introduced, and, during the addition, the pH was monitored continuously and when it approached the neutral range (pH 9) increased to pH 12 by addition of additional NaOH solution. After 6 h, the mixture was allowed to cool, 1.7 l of water were added and the mixture was extracted three times with in each case 500 ml of MTBE. The combined organic phases were washed with in each case 1500 ml of water and saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated. The residue was suspended in 500 ml of cyclohexane and heated to reflux, and undissolved particles were filtered off. The residue was once more extracted with 200 ml of boiling cyclohexane. The combined filtrates were concentrated to obtain the title compound. This gave 136.7 g of 3-(2,4-dichlorophenyl)-5-difluoromethoxy-1H-pyrazole as a solid. (Yield 47.3%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:25][C:26]1[C:31]([NH:32][CH3:33])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH2:20]([N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([F:25])=[C:31]([NH:32][CH3:33])[CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:24])[C:13]2=[O:23])[C:16]([CH3:22])=[N:17]1)[CH3:21]
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Reactant: CNc1cc(B2OC(C)(C)C(C)(C)O2)cnc1F
Product: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5cnc(F)c(NC)c5)cc4c32)c(C)n1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 0.078 mmol) and [2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methyl-amine (stage 150.1.1) to give the title compound as a yellow foam. (HPLC: tR 2.53 min (Method A); M+H=485 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.16 (s, 1H), 8.11-8.07 (m, 1H), 7.95-7.90 (m, 1H), 7.53-7.51 (m, 1H), 7.42-7.39 (m, 1H), 7.01-6.97 (m, 1H), 6.08 (q, br, 1H), 4.15 (q, 2H), 3.58 (s, 3H), 2.80 (d, 3H), 1.97 (s, 3H), 1.37 (t, 3H))
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:28][CH:27]5[NH:29][CH:24]([CH2:25][CH2:26]5)[CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(N(C(C)C)CC)(C)C.Cl[C:47]([O:49][CH2:50][CH3:51])=[O:48]>C(Cl)Cl.O>[CH2:50]([O:49][C:47]([N:29]1[CH:24]2[CH2:25][CH2:26][CH:27]1[CH2:28][N:22]([C:20]([C:17]1[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:36])[CH3:1])[N:30]([CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=1)=[O:21])[CH2:23]2)=[O:48])[CH3:51]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5)cn3)nc2n1C1CCCC1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1C2CCC1CN(C(=O)c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc1)C2
Temperature: 23 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
To a solution of 7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.205 mmol, 1.0 eq) and Diisopropylethylamine (0.071 mL, 0.409 mmol, 2.0 eq) in CH2Cl2 (5 mL) was added Ethyl Chloroformate (0.022 mL, 0.225 mmol, 1.1 eq) diluted in 3.0 mL of CH2Cl2. The reaction mixture was stirred at 23° C. for 1 hour then diluted with water. The organic was collected and dried over Na2SO4, filtered, and concentrated. The crude reaction was purified using silica gel chromatography which gave 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (25 mg) in 21% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.22-1.37 (m, 4H) 1.60 (br. s., 2H) 1.69-1.82 (m, 3H) 1.97 (br. s., 3H) 2.04-2.20 (m, 4H) 2.56 (d, J=8.59 Hz, 2H) 3.19 (s, 6H) 3.60 (br. s., 2H) 4.21 (q, J=7.07 Hz, 2H) 4.36 (br. s., 2H) 4.56 (br. s., 1H) 4.83 (t, J=8.59 Hz, 1H) 6.52 (s, 1H) 7.82 (dd, J=8.59, 2.02 Hz, 1H) 8.39 (d, J=2.02 Hz, 1H) 8.59 (d, J=8.59 Hz, 1H) 8.77 (s, 1H). HRMS m/z, (M+H)+: 561.2946.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]3[N:23]([Si](C(C)C)(C(C)C)C(C)C)[CH:24]=[CH:25][C:17]=23)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:36][NH2:37].CC(O)=O>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[N:36][NH2:37])[C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]3[NH:23][CH:24]=[CH:25][C:17]=23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)C3CCN(Cc4ccccc4)CC3)c(Cl)cnc21
Reactant: NN
Solvent: CC(=O)O
Product: NN=C(c1c(Cl)cnc2[nH]ccc12)C1CCN(Cc2ccccc2)CC1
Yield: 63.7 %

Procedure:
The mixture of (1-benzylpiperidin-4-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone (1.85 g, 3.63 mmol), anhydrous hydrazine (0.341 mL, 10.9 mmol) and AcOH (0.21 mL, 3.63 mmol) was heated at reflux over 3 Å molecular sieves in a Dean-Stark trap for about 48 h. The reaction mixture was cooled to ambient temperatures, the solvent was removed under reduced pressure and the residue partitioned between saturated NaHCO3 (100 mL) and EtOAc (100 mL). The organic layer was separated, washed with brine (100 mL), dried in vacuo over anhydrous MgSO4 and concentrated. The residue was suspended in Et2O (15 mL) and the resulting precipitate was collected by filtration and dried in vacuo to yield 4-((1-benzylpiperidin-4-yl)(hydrazono)methyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine (0.85 g, 64%) as an off-white solid: LC/MS (Table 2, Method n) Rt=1.48 min; MS m/z: 368 and 370 (M+H)+.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@@H:13]([CH3:22])[C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15].[P:23](Cl)(Cl)(=[O:31])[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)[Cl:35]>>[Cl:35][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][P:23](=[N:12][C@@H:13]([CH3:22])[C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15])=[O:31]
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: C[C@H](N)C(=O)OCC(C)(C)C
Reactant: ClCCl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: C[C@H](N=[P+]([O-])Oc1ccccc1Cl)C(=O)OCC(C)(C)C

Procedure:
Using the general procedure for synthesizing naphthyl (amino acid ester) phosphorochloridates, the tosylate salt of (S)-neopentyl 2-aminopropanoate (2.00 g, 6.03 mmol), phenyl phosphorodichloridate (0.90 mL, 12.06 mmol) and TEA (1.68 mL, 12.06 mmol) were combined in 66 mL of dry DCM. The product, (2S)-neopentyl 2-(chloro(phenoxy)phosphorylamino)propanoate was obtained as a clear, thick oil (1.91 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:14]23)[CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][NH:26][CH2:27][C@@H:14]23)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: O=Cc1cccc(Cl)c1
Product: Clc1cccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c1

Procedure:
Using 3-chlorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 156. 1H NMR(CDCl3) δ 7.37 (s, 1H), 7.29-7.20 (m, 2H), 6.34 (d, 1H, J=2.2 Hz), 6.24 (d, 1H, J=2.6 Hz), 4.25 (broad s, 2H), 3.67 (s, 2H), 3.57-3.50 (m, 1H), 3.42-3.31 (m, 2H), 3.20-2.85 (m, 6H), 2.60 (dd, 1H, J=12.8, 9.9 Hz), 2.15-1.97 (m, 2H). LRMS (ES)+: 386.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[N:25]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[N:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C(N)c1cccc(N)n1
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cccc(N)n1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(6-aminopyrid-2-yl)acetate (prepared from 2-(methoxyimino)-2-(6-aminopyrid-2-yl)acetic acid [CAS 71470-33-2] using General Procedures G and AC above), the title compound was prepared. The product was purified by LC 2000 preparative column chromatography using 1:1 EtOAc/hexanes as the eluent.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:32])=[C:15]([CH:31]=2)[C:16]([NH:18][C:19]2[C:28]([CH3:29])=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][C:20]=2[CH3:30])=[O:17])[CH2:6]1.CO>C1COCC1>[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:32])=[C:15]([CH:31]=2)[C:16]([NH:18][C:19]2[C:20]([CH3:30])=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][C:28]=2[CH3:29])=[O:17])[CH2:6]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCCC(CO)C3)ccc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N2CCCC(CO)C2)cc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
A solution of aqueous 4N NaOH (2.00 ml) is added to a stirred solution of methyl 4-[[5-[3-(hydroxymethyl)-1-piperidyl]-2-methyl-benzoyl]amino]-3,5-dimethyl-benzoate (0.3 g, 0.73 mmol) in THF:MeOH (10 ml:5 ml). After 16 hours at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 4 with 1N HCl, and extracted with 10% IPA in CH2Cl2. The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with diethyl ether and filtered to afford the title compound as a light brown solid (0.27 g, 90%). Mass spectrum (m/z): 397.2 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]3[C:14](=[CH2:23])[CH2:15][CH2:16][CH2:17][N:18]([S:19]([CH3:22])(=[O:21])=[O:20])[C:10]3=[N:9][C:8]=2[O:7][C:6]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:4].CNC(C1C2C=C3C(C)=CCCN(S(C)(=O)=O)C3=NC=2OC=1C1C=CC(F)=CC=1)=O.CO>[OH-].[OH-].[Pd+2].CCOC(C)=O>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]3[CH:14]([CH3:23])[CH2:15][CH2:16][CH2:17][N:18]([S:19]([CH3:22])(=[O:21])=[O:20])[C:10]3=[N:9][C:8]=2[O:7][C:6]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:4]
Reactant: C=C1CCCN(S(C)(=O)=O)c2nc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc21
Agent: [Pd+2]
Agent: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc3c(cc12)C(C)=CCCN3S(C)(=O)=O
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc3c(cc12)C(C)CCCN3S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The mixture of 2-(4-fluoro-phenyl)-9-methanesulfonyl-5-methylene-6,7,8,9-tetrahydro-5H-1-oxa-9,10-diaza-cyclohepta[f]indene-3-carboxylic acid methylamide and 2-(4-fluoro-phenyl)-9-methanesulfonyl-5-methyl-8,9-dihydro-7H-1-oxa-9,10-diaza-cyclohepta[f]indene-3-carboxylic acid methylamide (15 mg), Pd(OH)2 (20% on carbon, 4.9 mg), MeOH (0.56 ml) and EtOAc (0.14 ml) was stirred under hydrogen for 1.5 h at rt. The mixture was filtered through a 0.2 μM PTFE syringe filter and concentrated to give the title compound as an off-white solid. MS (ESI) m/z 432.3 (M+1). Retention time=1.23 min (Method A). 1H-NMR (400 MHz, CDCl3) δ ppm 8.13 (s, 1H), 7.94-7.86 (m, 2H), 7.31-7.23 (m, 2H), 5.88 (br, 1H), 3.51 (s, 3H), 3.39-3.31 (m, 1H), 2.10-1.62 (m, 6H), 1.49 (d, 3H).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([NH2:8])[CH2:6][NH2:7]>O>[CH2:5]([N:8]([CH2:3][CH2:2][C:1]#[N:4])[CH2:3][CH2:2][C:1]#[N:4])[CH2:6][N:7]([CH2:3][CH2:2][C:1]#[N:4])[CH2:3][CH2:2][C:1]#[N:4]
Reactant: NCCN
Reactant: C=CC#N
Solvent: O
Product: N#CCCN(CCC#N)CCN(CCC#N)CCC#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
Acrylonitrile (110 g, 137 cm3, 2.08 mol) was added to a vigorously stirred mixture of ethylenediamine (25 g, 27.8 cm3, 0.416 mol) and water (294 cm3) at 40° C. over 30 min. During the addition, it was necessary to cool the mixture with a 25° C. water bath to maintain temperature at 40° C. The mixture was then stirred for additional 2 hours at 40° C. and 2 hours at 80° C. Excess acrylonitrile and half of the water were evaporated off and the residue, on cooling to room temperature, gave a white solid which was recrystallised from MeOH-water (9:1) to give pure product 3,3′,3″,3′″-(ethane-1,2-diylbis(azanetriyl))tetrapropanenitrile (86.6 g, 76.4%) as white crystals, mp 63-65° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[O:19][CH3:20])[N:11]([CH2:21][CH2:22][F:23])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[F:23][CH2:22][CH2:21][N:11]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][C:16]=2[O:19][CH3:20]
Reactant: CCOC(=O)C1CCCc2c1c1c(OC)cccc1n2CCF
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc2c1c1c(n2CCF)CCCC1C(=O)O
Yield: 99.3 %

Procedure:
8-chloro-9-(2-Fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (16) (380 mg, 1.2 mmol) was dissolved in ethanol (4 mL). A solution of sodium hydroxide (580 mg, 14.5 mmol) dissolved in 6 mL of water, was added. The reaction mixture was heated to reflux overnight. The solvent was removed in vacuo and the crude mixture diluted with water, acidified with 2 N HCl until acidic, and washed with dichloromethane. The organics were combined and dried over magnesium sulfate and concentrated in vacuo to give 347 mg (quantitative) of 9-(2-Fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid (17) as an off white solid which was used crude into the next step. The structure was confirmed by 13C NMR (75 MHz; CDCl3): δC 20.4, 21.9, 27.2, 39.9, 43.3 (d, JCF=23 Hz), 55.1, 81.9 (d, JCF=173 Hz), 100.3, 102.8, 106.2, 117.1, 122.2, 135.6, 137.8, 153.3, and 180.8.
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:30])[C@H:16]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH:41]1[CH2:66][CH2:65][CH2:64][C@H:42]1[C:43]([NH:45][C@H:46]([C:50]([NH:52][C@H:53]([C:61]([NH2:63])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51])[CH:47]([CH3:49])[CH3:48])=[O:44].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:30])[C@H:16]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([N:41]1[CH2:66][CH2:65][CH2:64][C@H:42]1[C:43]([NH:45][C@H:46]([C:50]([NH:52][C@H:53]([C:61]([NH2:63])=[O:62])[CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:51])[CH:47]([CH3:48])[CH3:49])=[O:44])=[O:25])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C)C(C)C
Reactant: CC(C)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(N)=O)C(C)C)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
25 g (43.3 mmol) of Z-Val-Val-MeVal-Pro-OH and 15.59 g (43.3 mmol) of H-Pro-Val-Phe-NH2 were suspended in 430 ml of dry dichloromethane. After cooling to 0° C., 5.81 ml (52 mmol) N-methylmorpholine, 1.97 g (15 mmol) of HOBt and 8.33 g (43.3 mmol) of EDCI were added and the reaction mixture stirred overnight at room temperature. The solvents were evaporated, the residue dissolved in 640 ml of dichloromethane and thoroughly washed with saturated aqueous NaHCO3 solution (4×), water (1×), 5% citric acid (3×) and saturated NaCl solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to yield 33.04 g of the product. The crude product was chromatographed on a silica gel column with 20% MeOH/hexane. 18.32 g of the desired product were obtained.