Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][CH2:41][NH2:42].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][CH2:41][NH:42][C:17]([C:16]1[CH:20]=[CH:21][C:13]([O:12][C:11]2[CH:10]=[C:9]3[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]3)=[CH:3][C:2]=2[Cl:1])=[CH:14][CH:15]=1)=[O:19]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCc1ccccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccccc4Br)cc3)c(Cl)cc21
Reaction time: 0.33 h
Yield: 90.4 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (200 mg, 0.531 mmol) was diluted with DCM (3 mL) followed by the addition of oxalyl chloride in DCM (2M) (292 μl, 0.584 mmol) and DMF (1 drop). After stirring for 20 minutes, 2-(2-bromophenyl)ethanamine (117 mg, 0.584 mmol) and DIEA (203 μl, 1.17 mmol) were added and the reaction was stirred at ambient temperature for 12 hours. The reaction was loaded directly onto a biotage 25 cartridge and eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes to yield ethyl 7-(4-(2-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (268 mg, 0.480 mmol, 90.3% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@:5]([CH3:39])([C:14]([NH:16][NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=2)=O)[CH2:4][O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:50])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:40])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@:5]([CH3:39])([C:14]2[S:50][C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=3)=[N:17][N:16]=2)[CH2:4][O:3]1
Reactant: CCCCCCCCOc1ccc(C(=O)NNC(=O)[C@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2nnc([C@@]3(C)COC(C)(C)N3C(=O)OC(C)(C)C)s2)cc1C(F)(F)F
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of (S)-tert-butyl 2,2,4-trimethyl-4-(2-(4-(octyloxy)-3-(trifluoromethyl)-benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylate (13a) (228 mg, 0.39 mmol) in toluene (5 mL) was treated with Lawesson's reagent (473 mg, 1.17 mmol) at 85° C. for 2 hours. The reaction was cooled down to room temperature and the supernatant was chromatographed on a silica gel column eluted with ethyl acetate-hexane (0-30%, v/v) to afford the title compound (156 mg, 70% yield). MS (ESI): 572.17 (MH+), 1H NMR (400 MHz, CDCl3) δ 8.10 (d, 1H, J=8.8 Hz), 8.08 (d, 1H, J=6.8 Hz), 7.06 (d, 1H, J=8.0 Hz), 4.41 (d, 1H, J=8.0 Hz), 4.18 (d, 1H, J=9.6 Hz), 4.13-4.07 (m, 3H), 2.00 (s, 3H), 1.85 (m, 2H), 1.78 (s, 3H), 1.68 (m, 4H), 1.51 (s, 3H), 1.47 (m, 2H), 1.39-1.28 (m, 13H), 0.89 (t, 3H, J=7.2 Hz).
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6]([CH2:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[C:7](=[O:23])[N:8]2[CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:44]([C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1)#[N:45]>C1(C)C=CC=CC=1.CCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:10]1[C:2]([C:49]2[CH:50]=[CH:51][C:46]([C:44]#[N:45])=[CH:47][CH:48]=2)=[CH:3][CH:4]=[C:5]2[C:9]=1[N:8]([CH2:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=1)[C:7](=[O:23])[C:6]2([CH2:31][C:32]1[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=1)[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1c(Br)ccc2c1N(Cc1ccc3ccccc3c1)C(=O)C2(Cc1ccncc1)Cc1ccncc1
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: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(C#N)cc2)ccc2c1N(Cc1ccc3ccccc3c1)C(=O)C2(Cc1ccncc1)Cc1ccncc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of 6-bromo-7-methyl-1-naphthalen-2-ylmethyl-3,3-bis-pyridin-4-ylmethyl-1,3-dihydro-indol-2-one (200 mg, 0.365 mmol) in 4 ml of toluene and 2.5 ml of EtOH was added tetrakis(triphenylphosphine)palladium (17 mg, 0.015 mmol) under an atmosphere of dry N2, followed by the addition of a solution of aqueous sodium carbonate (Na2CO3) (77 mg, 0.738 mmol) dissolved in 2 ml of water and 4-cyanobenzene boronic acid (101 mg, 0.686 mmol). The reaction mixture was heated to 100° C. and stirred at this temperature overnight. The reaction mixture was concentrated under vacuum and then partitioned between DCM and saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated under vacuum to give the crude product. It was chromatographed on silica gel eluting MeOH/NH4OH/CHCl3/(3/0.3/97) to give the titled compound of Example 10 (194 mg, 93% yield).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1C=CC=CC=1)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.N1C=CC=CC=1.[CH3:62][N:63]1C=C(S(Cl)(=O)=O)[N:65]=[CH:64]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([C:42]1[N:65]=[CH:64][N:63]([CH3:62])[CH:43]=1)(=[O:40])=[O:41])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cn1cnc(S(=O)(=O)NCCc2c(CCOc3ccc(C(=O)O)cc3)c3cc(Cl)ccc3n2C(c2ccccc2)c2ccccc2)c1
Yield: 92 %

Procedure:
To methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) (1.0 equiv) and Et3N (3.0 equiv) or pyridine (3.0 equiv) in CH2Cl2 (0.05 M) was added 1-methylimidazole-4-sulfonyl chloride (1.2 equiv). The reaction was monitored by TLC (10% MeOH—CH2Cl2) and was heated if necessary. After 30 min the mixture was poured into saturated sodium bicarbonate and extracted with CH2Cl2. The combined organic phase was washed with brine, dried over sodium sulfate and purified by column chromatography to afford 92% of the desired product.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.[CH3:29][C:30]([CH3:36])([CH2:34][OH:35])[C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:35][CH2:34][C:30]([CH3:36])([CH3:29])[C:31]([N:26]1[CH2:25][CH:24]=[C:23]([C:21]2[NH:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]5[N:6]=[CH:5][S:4][C:8]=5[CH:9]=4)[C:15]=3[CH:22]=2)[CH2:28][CH2:27]1)=[O:32]
Reactant: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Reactant: CC(C)(CO)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)C(=O)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine trihydrochloride (50.0 mg, 0.11 mmol) in DMF (3 mL) was added 2,2-dimethyl-3-hydroxypropionic acid (150 mg, 1.3 mmol), TBTU (42.0 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.50 mmol). The reaction mixture stirred at rt for 16 h. The mixture was concentrated in vacuo and purified via MDP, which afforded the title compound as yellow solid. MS (ES+): m/z: 448.96 (100) [MH+]. HPLC: tr=2.35 min (ZQ2000: polar—5 min). 1H NMR (400 MHz, DMSO-d6): δ=1.20 (s, 6H), 3.19 (s, 1H), 3.46 (s, 2H), 3.79-3.81 (m, 2H), 4.21 (s, 2H), 4.59 (bs, 1H), 6.43 (s, 1H), 6.84 (d, J=1.6 Hz, 1H), 7.87 (dd, J=1.6, 8.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 8.34 (s, 1H), 8.91 (d, J=2.0 Hz, 1H), 9.23 (s, 1H), 9.62 (s, 1H), 12.03 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:12]1>C(#N)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:11][CH:12]=2)(=[O:21])=[O:22])=[O:25])[N:7]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1csc2ccccc12
Solvent: CC#N
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2csc3ccccc23)n1
Temperature: 25 °C

Procedure:
To 25 ml of anhydrous acetonitrile containing 1.4 g of 2-amino-4-methoxy-6-methylpyrimidine was added 2.4 g of benzothiophene-3-sulfonyl isocyanate with stirring. The mixture was heated to boiling, allowed to cool to room temperature and then stirred overnight. The resultant precipitate was filtered off and washed with ether to yield 2 g of the desired product, m.p. 180°-181° C. It showed absorption by NMR (60 MC) at 2.24 δ (6-CH3 group), 3.8 δ (4-OCH3), 6.2 δ (5-H on pyrimidine), 7-8 δ (aryl H's on benzo) and 8.3 δ (H on thiophene portion).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])#[CH:2]>CCO.[OH-].[OH-].[Pd+2]>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH3:2]
Reactant: C#Cc1ccc(C(=O)O)cc1OCCCOC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccc(C(=O)O)cc1OCCCOC
Reaction time: 0.25 h

Procedure:
To a solution of 4-ethynyl-3-(3-methoxy-propoxy)-benzoic acid (1 g, 4.11 mmol) in EtOH (20 mL), Pd(OH)2 (0.1 g) is added. The resulting mixture is stirred under an hydrogen atmosphere for 15 min, then filtered and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: hexane/AcOEt 2:1) to give the title compound as white powder. 1H-NMR (CDCl3, 300 MHz): δ=1.2 (t, 3H), 2.15 (p, 2H), 2.7 (q, 2H), 3.38 (s, 3H), 3.62 (t, 2H), 4.15 (t, 2H), 7.25 (d, 1H), 7.55 (s, 1H), 7.68 (d, 1H) ppm.
Reaction SMILES: C[Al](C)C.[CH3:5][NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]([C:17]1[C:22]2[N:23]=[C:24]([C:26]([O:28]CC)=O)[O:25][C:21]=2[C:20]([F:31])=[C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:18]=1[CH3:38])#[N:16].Cl>ClCCl>[C:15]([C:17]1[C:22]2[N:23]=[C:24]([C:26]([N:6]([CH3:5])[CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:28])[O:25][C:21]=2[C:20]([F:31])=[C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:18]=1[CH3:38])#[N:16]
Reactant: CNCCc1ccccc1
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)CCc3ccccc3)nc2c1C#N
Reaction time: 0.42 h

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution, 1.80 ml, 1.85 mmol) was dropwise added at room temperature to a dichloromethane (3 ml) solution of N-methylphenethylamine (269 μl, 1.85 mmol), and stirred for 25 minutes. Subsequently, a dichloromethane (3 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (300 mg, 925 μl) was dropwise added and stirred for 14.5 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature, and the reaction liquid was extracted with chloroform.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([N:21]3[C:29]4[C:24](=[CH:25][C:26]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:36]N(C=O)C.CI>[Cl-].[Na+].O.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:15]2[CH:20]=[C:19]([N:21]3[C:29]4[C:24](=[CH:25][C:26]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[N:18]=[CH:17][N:16]=2)[CH3:36])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: ClCCl
Product: CN(c1cc(N2CCc3cc(S(C)(=O)=O)ccc32)ncn1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6b (80 mg, 0.17 mmol), NaH (75 mg, 1.87 mmol) and DMF (1 mL) was stirred at room temperature for 30 minutes. Methyl iodide (0.025 mL, 0.4 mmol) was added and the mixture was heated at 90° C. in a sealed vial for 18 h. After cooling to room temperature, DCM (4 mL) and brine (4 mL) were added. The layers were separated and the aqueous layer was extracted with DCM (3×3 mL). The combined extracts were dried, filtered, evaporated and purified by preparative HPLC to give 16-1, LCMS 488.4 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([O:11][CH2:12][C:13](O)=[O:14])([CH3:10])([CH3:9])[CH3:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:7]([O:11][CH2:12][C:13]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:14])([CH3:10])([CH3:9])[CH3:8]
Reactant: C1COCCN1
Reactant: CC(C)(C)OCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
Morpholine (2.98 ml, 34.4 mmol), tert-Butoxy-acetic acid (4.485 g, 34.4 mmol) and HATU (13.093 g, 34.4 mmol) were dissolved in 15 ml dimethylformamide. The reaction mixture was stirred overnight at ambient temperature. It was extracted with ethyl acetate and the organic phase was washed with water, sodium bicarbonate solution, 1M HCl solution and finally with brine. The organic phase was dried over sodium sulfate, filtered, and concentrated to give 2-tert-Butoxy-1-morpholin-4-yl-ethanone (2.170 g, 10.78 mmol).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([F:14])[CH:5]=1)#N.C([O:17]CC)C>>[F:14][C:6]1[CH:5]=[C:4]([CH:2]=[O:17])[CH:9]=[CH:8][C:7]=1[NH:10][C:11](=[O:13])[CH3:12]
Reactant: CCOCC
Reactant: CC(=O)Nc1ccc(C#N)cc1F
Agent: Cl
Product: CC(=O)Nc1ccc(C=O)cc1F
Reaction time: 8 h
Yield: 98 %

Procedure:
Stannous chloride (98%, 17.3 g, 91.5 mmol) was placed in a dry 3-neck 500 mL round bottom flask under argon. Anhydrous diethyl ether (100 mL) was added via cannula. The suspension was stirred as dry HCl gas was bubbled in until the solid dissolved. Anhydrous methylene chloride (100 mL) was added via cannula to homogenize the two layers and the solution was stirred for an additional 0.5 h while a continuous stream of dry HCl gas was bubbled through the solution. N-(4-Cyano-2-fluoro-phenyl)-acetamide (10.5 g, 58.7 mmol) was added and the suspension stirred at rt for an additional 3 h under a continuous stream of dry HCl gas. During this time a sticky, yellow solid formed which eventually crystallized. The reaction mixture was left standing overnight after the introduction of HCL was stopped. The residue was partioned between methylene chloride (100 mL) and water (100 mL) and the phases were separated. The aqueous phase was extracted with methylene chloride (100 mL) and the combined organic extracts were washed with brine (100 mL) and dried over anhydrous potassium carbonate (essential for purity of the product). Concentration of the solvent provided 10.5 g (57.7 mmol) of a crystalline residue. Yield: 98%; mp 133° C.; 1H NMR (400 MHz, CDCl3) δ 10.1 (s, 1H, NH), 9.9 (s, 1H, CHO), 8.39 (t, J=8.0 Hz, 1H), 7.76–7.72 (m, 2H), 2.18 (s, 3H, Me).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([N:11]([CH3:17])[CH2:12][CH2:13][CH2:14]2)[CH2:9]1)C1C=CC=CC=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CO.[Pd]>[CH3:17][N:11]1[CH2:12][CH2:13][CH2:14][CH:15]2[CH2:16][NH:8][CH2:9][CH:10]12
Reactant: CN1CCCC2CN(Cc3ccccc3)CC21
Agent: [Pd]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: CN1CCCC2CNCC21

Procedure:
11.7 g (54 mmol) of 6-benzyl-1-methyl-octahydropyrrolo[3,4-b]pyridine as the dihydrochloride are hydrogenated in 100 ml of methanol over palladium-on-active charcoal in accordance with the working instructions of Example Id. Working up by distillation gives 2.6 g (34% of theory) of a colorless oil of boiling point 83°-85°/12 mbar).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[C:5]=2[N:6]=1.[C:23]1([CH:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:30]I)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:30][S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:5]=3[N:6]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CCOc1cccc2c1CCc1sc(S)nc1-2
Reactant: ICC(c1ccccc1)c1ccccc1
Product: O=C(O)CCOc1cccc2c1CCc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 29 %

Procedure:
Using ethyl 3-[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]propionate and 2,2-diphenylethyl iodide, the procedure of Example 21 was otherwise repeated to synthesize the title compound. Yield 29%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15](O)=[O:16])=[CH:10]3)[C:6]=2[CH:18]=1.C(Cl)(C([Cl:23])=O)=O.CN(C)C=O>C(#N)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]([Cl:23])=[O:16])=[CH:10]3)[C:6]=2[CH:18]=1
Reactant: O=C(O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
Into a 10000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (450 g, 1.46 mol, 1.00 equiv) in ACN (4500 mL), followed by the addition of (COCl)2 (450 mL) dropwise with stirring at 0° C. over 45 min. To this was added N,N-dimethylformamide (5 mL). The resulting solution was stirred at room temperature for 7 h, diluted with 2000 mL of DCM and concentrated under vacuum to afford 450 g (94%) of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonyl chloride as a gray solid.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)C.[OH-].[Na+]>C(O)C.O.C(OCC)C.CCCC(C)C>[CH2:26]([O:25][C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[C:13]1[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:33])=[O:3])[CH:7]=2)=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)Cc1cccc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCCC(C)C
Product: O=C(O)Cc1cccc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccccc2)c1
Yield: 80.2 %

Procedure:
A solution of (2-benzyloxy-5-chloro-[1,1′;2′,1″]terphenyl-3″-yl)-acetic acid ethyl ester (112 mg, 0.25 mmol) in ethanol (5 ml) and 2M sodium hydroxide (1 ml, 2 mmol) was stirred at room temperature for 1 hour then diluted with water and 1:1 diethyl ether/iso-hexane. The aqueous suspension was separated, acidified with 1M hydrochloric acid and extracted with diethyl ether. The organic solution was dried (MgSO4) evaporated to dryness and the residue triturated with iso-hexane to give the title compound as a white solid (86 mg, 80%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:46])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[C:41]4[C:36](=[CH:37][C:38]([O:44][CH3:45])=[C:39]([O:42][CH3:43])[CH:40]=4)[N:35]=[CH:34][N:33]=3)=[CH:27][CH:26]=2)=[CH:18][C:17]=1[CH:47]=O.[CH:49]([NH2:52])([CH3:51])[CH3:50].C(OC)(OC)OC>C(Cl)Cl.CO>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:46])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[C:41]4[C:36](=[CH:37][C:38]([O:44][CH3:45])=[C:39]([O:42][CH3:43])[CH:40]=4)[N:35]=[CH:34][N:33]=3)=[CH:27][CH:26]=2)=[CH:18][C:17]=1[CH2:47][NH:52][CH:49]([CH3:51])[CH3:50]
Reactant: COc1cc2ncnc(Oc3ccc(CC(=O)Nc4ccc(Cl)c(C=O)c4)cc3)c2cc1OC
Reactant: CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: COC(OC)OC
Solvent: CO
Product: COc1cc2ncnc(Oc3ccc(CC(=O)Nc4ccc(Cl)c(CNC(C)C)c4)cc3)c2cc1OC
Yield: 35.5 %

Procedure:
Sodium triacetoxyborohydride (0.072 g) was added portionwise to a stirred mixture of N-(4-chloro-3-formylphenyl)-2-[4-(6,7-dimethoxyquinazolin-4-oxy)phenyl]acetamide (0.08 g), isopropylamine (0.021 g), trimethyl orthoformate (0.2 ml), methanol (0.2 ml) and methylene chloride (0.6 ml) and the resultant mixture was stirred at ambient temperature for 12 hours. The mixture was evaporated and the residue was purified by preparative HPLC using a Waters ‘β Basic Hypersil’ reversed-phase column (5 microns silica, 20 mm diameter, 100 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound as a solid (0.031 g); 1H NMR: (DMSOd6) 1.03 (d, 6H), 1.88 (br s, 1H), 2.71-2.8 (m, 1H), 3.7 (s, 2H), 3.72 (br s, 2H), 3.97 (s, 3H), 3.99 (s, 3H), 7.26 (d, 2H), 7.32 (d, 1H), 7.39 (s, 1H), 7.44 (d, 2H), 7.55 (s, 1H), 7.64 (m, 1H), 7.73 (d, 1H), 8.53 (s, 1H), 10.34 (s, 1H); Mass Spectrum: M+H+ 521 and 523.
Reaction SMILES: O[C@H](CC)[C@@H](N([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)C(OC)=O)C(O)=O.O[C@@H:27]([CH2:49][CH3:50])[C@@H:28]([N:32]([C:37]1C=CC(C2C=CC=CC=2)=CC=1)[C:33]([O:35]C)=[O:34])[C:29]([OH:31])=[O:30].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:18]1([C:15]2[CH:14]=[CH:13][C:12]([O:35][C:33](=[O:34])[N:32]([CH3:37])[C@H:28]3[C:29](=[O:31])[O:30][C@@H:27]3[CH2:49][CH3:50])=[CH:17][CH:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC[C@@H](O)[C@H](C(=O)O)N(C(=O)OC)c1ccc(-c2ccccc2)cc1
Reactant: CC[C@H](O)[C@H](C(=O)O)N(C(=O)OC)c1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H]1OC(=O)[C@@H]1N(C)C(=O)Oc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 57 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3R*)-3-hydroxy-2-[(4-phenylphenyl)-methoxycarbonylamino]-pentanoic acid and (2R*,3S*)-3-hydroxy-2-[(4-phenylphenyl)-methoxycarbonylamino]-pentanoic acid (0.193 g, 0.56 mmol) in dry CH2Cl2 (25.0 mL), at 0° C., Et3N (0.235 mL, 1.69 mmol) and subsequently TBTU (0.217 g, 0.67 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy/AcOEt (from 90:10 to 80:20) to afford the pure title compound (0.089 g, 57%), as pure anti diastereoisomer, as white solid. MS (ESI) m/z: 343 [M−NH4]+; (ESI) m/z: 324 [M−H]−. 1H NMR (DMSO-d6) δ 0.92 (t, J=7.38 Hz, 3H), 1.68-1.94 (m, 2H), 4.49-4.60 (m, 1H), 4.76 (dd, J=4.32, 8.08 Hz, 1H), 5.12 (s, 2H), 7.33-7.42 (m, 1H), 7.42-7.53 (m, 4H), 7.62-7.76 (m, 4H), 8.25 (d, J=8.09 Hz, 1H).