Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3]1.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(N(C(C)C)CC)(C)C>CC#N>[CH3:1][C@@H:2]1[CH2:3][N:4]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:6][N:7]1[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: C[C@@H]1CN(C2CCCCC2c2ccccc2)CCN1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H]1CN(C2CCCCC2c2ccccc2)CCN1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.5 %

Procedure:
To a solution of (3R)-3-methyl-1-(2-phenylcyclohexyl)piperazine (900 mg, 3.48 mmol) (crude) in MeCN was added tert-butyl 2-bromoacetate (0.815 g, 4.18 mmol) followed by diisopropylethylamine (1.21 ml, 6.97 mmol). The reaction was stirred at RT for 5 h. The solvent was evaporated under high vacuum and the residue was loaded on column (SiO2, hexane to hexane/EtOAc=100:10 to 100:20 to 100:30 to 100:40) to give tert-butyl 2-((R)-2-methyl-4-(2-phenylcyclohexyl)piperazin-1-yl)acetate (1.16 g, 89.4% yield) as a gum.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[C:32]1[C:33]([O:42][CH3:43])=[CH:34][C:35]([O:40][CH3:41])=[C:36]([CH:39]=1)[CH:37]=O)(=O)C.N1C2C(=CC=CC=2)C=C1C1C(OC)=CC(OC)=C(C=1)C=O>>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[C:32]1[C:33]([O:42][CH3:43])=[CH:34][C:35]([O:40][CH3:41])=[C:36](/[CH:37]=[CH:2]/[C:1]([C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)(=[O:12])=[O:11])=[CH:8][CH:9]=2)=[O:3])[CH:39]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccccn2)cc1
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C(C)=O)cc1C=O
Agent: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1C=O
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)Nc2ccccn2)cc1

Procedure:
NH4Cl (25 mL) and transferred to a separatory funnel containing THF (50 mL), EtOAc (50 mL) and H2O (50 mL). The layers were cut and the organic layer was concentrated to dryness. The crude product was suspended in EtOH (50 mL), filtered and then dried under vacuum to afford 2.5 g (85% yield) of the title compound, analytical dada identical as above. Similarly, the title compound could be prepared from 4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A) and 5-(1-acetyl-1H-indol-2-yl)-2,4-dimethoxybenzaldehyde (Ex-57F) or 5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehyde (Ex-57D or Ex-57DD).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)=[O:4].[O:10]=[C:11]([O:29][C@@H:30]1[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)[CH:12]([NH:19][C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25]([O:27][CH3:28])=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOC(C)=O>[Br-:1].[CH3:28][O:27][C:25]([C:21]1[S:22][CH:23]=[CH:24][C:20]=1[NH:19][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:11]([O:29][C@@H:30]1[CH:35]2[CH2:34][CH2:33][N+:32]([CH2:2][C:3](=[O:4])[C:5]3[CH:9]=[CH:8][S:7][CH:6]=3)([CH2:37][CH2:36]2)[CH2:31]1)=[O:10])=[O:26]
Reactant: O=C(CBr)c1ccsc1
Reactant: COC(=O)c1sccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1sccc1NC(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccsc3)CCC1CC2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
2-Bromo-1-(thiophen-3-yl)ethanone (25.6 mg, 0.12 mmol) was added to a solution of methyl 3-(2-oxo-1-phenyl-2-((R)-quinuclidin-3-yloxy)ethylamino)thiophene-2-carboxylate (C11) (50 mg, 0.12 mmol) in EtOAc (2 ml). The reaction mixture was stirred at room temperature overnight, and then the solvent was evaporated under vacuum. The residue was triturated with Et2O and then purified by preparative HPLC (Eluent: CH3CN/H2O) to obtain (3R)-3-(2-(2-(methoxycarbonyl)thiophen-3-ylamino)-2-phenylacetoxy)-1-(2-oxo-2-(thiophen-3-yl)ethyl)-1-azoniabicyclo[2.2.2]octane bromide (44.3 mg, 58.6% yield).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16]3=[C:17]([CH2:19][S:20][CH2:21][CH2:22][N:15]3[C@H:14]3[CH2:23][CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][C@@H:13]23)[CH:18]=1>>[CH2:1]([NH:9][C:10]1[CH:11]=[C:12]2[C:16]3=[C:17]([CH2:19][S:20][CH2:21][CH2:22][N:15]3[C@H:14]3[CH2:23][CH2:24][NH:25][CH2:26][C@@H:13]23)[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: c1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)cc1

Procedure:
Using benzaldehyde 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 171. 1H NMR (CDCl3) δ: 7.42-7.25 (m, 5H), 6.37 (d, 1H, J=1.8 Hz), 6.26 (d, 1H, J=2.2 Hz), 4.27 (s, 2H), 3.69 (ABq, 2H, JAB=15.2 Hz), 3.60-3.50 (m, 1H), 3.37-3.30 (m, 1H), 3.28-3.20 (m, 1H), 3.10-2.85 (m, 6H), 2.62 (dd, 1H, J=12.8, 9.1 Hz), 1.89-1.80 (m, 2H). LRMS (ES)+: 352.4 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=3)=[N:6]2)[CH2:2][CH2:3]1
Reactant: CSc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1
Reactant: CN1CCNCC1
Product: CSc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC3CC3)n2)cc1
Yield: 85.7 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and 1-methyl-piperazine were reacted to yield the title compound as a yellow oil (yield: 85.7%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][OH:14].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH:13]=[O:14]
Reactant: OCCCc1ccc2ccccc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCCc1ccc2ccccc2c1
Yield: 53 %

Procedure:
Then, following a procedure similar to that described in the second part of Preparation 4, the whole of this 3-(2-naphthyl)propanol was reacted with 2.06 g of dimethyl sulfoxide, 3.35 g of oxalyl chloride and 7.34 ml of triethylamine in 45 ml of methylene chloride. The reaction mixture was worked up and purified as described in the second part of Preparation 4, to give 1.74 g (yield 53%) of 3-(2-naphthyl)propanal as a colorless oil.
Reaction SMILES: [F-:1].[K+].I([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])=[O:14])=[O:10])(=O)=O.C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[F:1][C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])=[O:14])=[O:10]
Reactant: [F-]
Reactant: O=C(CNC(=O)c1ccc([N+](=O)[O-])c(I(=O)=O)c1)OCC(Cl)(Cl)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])c(F)c1)OCC(Cl)(Cl)Cl
Temperature: 97.5 °C
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
A mixture of spray-dried KF (135 mg, 2.3 mmol), intermediate 8 (120 mg, 0.23 mmol) and catalytic amount of 18-crown-6 in DMSO (5 mL) was stirred at 95-100° C. for 15 min. Work-up of the reaction mixture as described in example 1 gave the product as a yellow color solid (57 mg, 65%), mp 142-144° C. 1H NMR (400 MHz, CDCl3): δ 8.15 (1H, t, J=7.8 Hz), 7.78 (1H, dd, J=10.8, 1.6 Hz), 7.71 (1H, d, J=8.4 Hz), 6.70 (1H, br s), 4.86 (2H, s), 4.44 (2H, d, J=5.2 Hz); LC-MS (negative ion mode): m/z 371, 373 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH:18]=[C:17]2[C@@H:7]([CH2:8][C:9]3[C:19]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]2=4)[NH:11][CH:10]=3)[N:5]([CH3:6])[CH2:4]1.CN(C)C=O>[Pd].N1C=CC=CC=1>[OH:1][CH2:2][C@@H:3]1[CH:18]=[C:17]2[C@@H:7]([CH2:8][CH:9]3[C:19]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]2=4)[NH:11][CH2:10]3)[N:5]([CH3:6])[CH2:4]1
Reactant: CN1C[C@H](CO)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CN1C[C@H](CO)C=C2c3cccc4c3C(CN4)C[C@H]21

Procedure:
catalytically hydrogenating under a pressure of 1 to 5 bar, a reaction mixture comprising lysergol and least one aprotic solvent containing a tertiary nitrogen a solvent mixture of N,N-dimethylformamide and pyridine and a 5 to 10% palladium catalyst applied on activated carbon, at a temperature between 40° C. and the boiling point of the reaction mixture, to form dihydrolysergol; and
Reaction SMILES: Br[C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:11]=[C:10]3[C:26]2[CH:31]=[N:30][CH:29]=[C:28]([CH:32]3[CH2:34][CH2:33]3)[N:27]=2)=[N:5][N:6]=1.[NH:35]1[CH:39]=[CH:38][C:37](B(O)O)=[N:36]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:32]1([C:28]2[N:27]=[C:26]([C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[C:7]([C:4]5[O:3][C:2]([C:37]6[NH:36][N:35]=[CH:39][CH:38]=6)=[N:6][N:5]=5)[CH:8]=4)[N:12]([S:16]([C:19]4[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=4)(=[O:18])=[O:17])[CH:11]=3)[CH:31]=[N:30][CH:29]=2)[CH2:34][CH2:33]1
Reactant: OB(O)c1cc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(Br)o4)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(-c5ccn[nH]5)o4)ccc32)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 41.1 %

Procedure:
A brown mixture of 2-bromo-5-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazole (48.4 mg, 0.090 mmol), 1H-pyrazol-3-ylboronic acid (J&W Pharmlab, LLC, Levittown, Pa.; 30.3 mg, 0.271 mmol), Pd(PPh3)4 (20.85 mg, 0.018 mmol), and potassium carbonate (37.4 mg, 0.271 mmol) in a mixture of dioxane (1.0 mL) and H2O (0.250 mL) was stirred under argon at 100° C. for 1.5 h. The mixture was cooled to RT, concentrated onto silica gel, and purified chromatographically (silica gel, 0-100% (10% MeOH-EtOAc)/Hex) to provide 2-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-5-(1H-pyrazol-5-yl)-1,3,4-oxadiazole (19.6 mg, 0.037 mmol, 42%) as a light-yellow solid: MS (ESI, pos. ion) m/z: 524.2 (M+1).
Reaction SMILES: [F:1][C@H:2]1[C@@H:8]([O:9]S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:7][CH2:6][N:5]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:4][CH2:3]1.O[C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[C:37]([C:40]1[N:44]3[CH:45]=[C:46]([C:49]#[N:50])[CH:47]=[CH:48][C:43]3=[N:42][N:41]=1)[CH:36]=[CH:35]2>>[C:49]([C:46]1[CH:47]=[CH:48][C:43]2[N:44]([C:40]([C:37]3[CH:36]=[CH:35][C:34]4[C:39](=[C:30]([O:9][C@H:8]5[C@H:2]([F:1])[CH2:3][CH2:4][N:5]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:6][CH2:7]5)[CH:31]=[CH:32][CH:33]=4)[N:38]=3)=[N:41][N:42]=2)[CH:45]=1)#[N:50]
Reactant: N#Cc1ccc2nnc(-c3ccc4cccc(O)c4n3)n2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](Oc2cccc3ccc(-c4nnc5ccc(C#N)cn45)nc23)CC1

Procedure:
Prepared according to the method of Example 90, using cis-tert-butyl 4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate in place of trans-tert-butyl 4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate and 3-(8-hydroxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile in place of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol in Step C and running the reaction at 50° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[N:3]=1.[B:14]1([OH:24])[C:18]2[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]=2[CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:24][B:14]1[C:18]2[CH:19]=[CH:20][C:21]([O:23][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[N:3]=3)=[CH:22][C:17]=2[CH2:16][O:15]1
Reactant: OB1OCc2cc(O)ccc21
Reactant: CC(C)Oc1nc(Cl)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1nc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 80 °C
Yield: 25.5 %

Procedure:
To a mixture of 6-chloro-2-isopropoxy-nicotinonitrile (0.73 g, 4.0 mmol) and 3H-Benzo[c][1,2]oxaborole-1,5-diol (0.40 g, 2.66 mmol) in DMF (10 mL) was added potassium carbonate (1.10 g, 7.98 mmol). The resulting suspension was heated at 80° C. overnight. DMF was removed under reduced pressure, the residue was diluted with EtOAc (50 mL), washed with water (10 mL) and brine (2×10 mL), dried over Na2SO4, filtered, and concentrated to give brown oil. Purification was accomplished by reverse phase preparative HPLC using MeOH/H2O (0.1% AcOH) as the eluent to yield the title compound (0.21 g, 21%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.27 (s, 1 H), 8.23 (d, J=8.6 Hz, 1 H), 7.79 (d, J=7.8 Hz, 1H), 7.29 (s, 1 H), 7.22-7.14 (m, 1 H), 6.70 (d, J=8.2 Hz, 1 H), 4.99 (s, 2 H), 4.85 (sept., J=6.3 Hz, 1 H), 1.19 (d, J=6.3 Hz, 6 H); MS (ES) m/z: 311 (M+1)+; HPLC purity 98.44% (Maxplot), 97.99% (220 nm).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(OC)cc2OC)c(C)c1
Temperature: 25 °C

Procedure:
Methyl 4-bromo-3-methylbenzoate obtained in step 1 (3 g; 13.10 mmol), 2,4-dimethoxyphenylboronic acid (2.62 g; 14.4 mmol), potassium carbonate (9.05 g; 65.48 mmol), tetrakis(triphenylphosphine)palladium(0) (1.51 g; 1.31 mmol) were taken in toluene (15 mL) and water (15 mL) under N2 atmosphere. The reaction mixture was purged with vacuum and degassed with N2 and then refluxed for 6 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene (200 mL). The filtrate was concentrated to afford a brown oil which was taken in EtOAc (300 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 solution (100 mL), water (100 mL) and brine (100 mL), dried over MgSO4 and concentrated affording the title compound as a brown oil that was used without further purification (3.7 g, 98%). HPLC (Method A) Rt 4.74 min (Purity: 59.9%).
Reaction SMILES: [C:1](=[NH:26])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[C:8]([F:25])[CH:7]=1)[NH2:2].[OH:27]/[CH:28]=[C:29](/[CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[N:39][CH:40]=1)\[C:30](OC)=O.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:9]2[C:10]([F:12])=[CH:11][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:30]=[C:29]([CH2:34][C:35]4[CH:40]=[N:39][CH:38]=[N:37][CH:36]=4)[C:28](=[O:27])[N:26]=3)=[CH:7][C:8]=2[F:25])=[CH:15][C:16]=1[C:21]([F:22])([F:24])[F:23]
Reactant: N=C(N)OCCc1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Reactant: COC(=O)/C(=C\O)Cc1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=c1nc(OCCc2cc(F)c(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)[nH]cc1Cc1cncnc1
Temperature: 160 °C
Yield: 27 %

Procedure:
The mixture of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3,5-difluorophenyl)ethyl imidocarbamate (450 mg, 0.826 mmol), methyl (2Z)-3-hydroxy-2-(5-pyrimidinylmethyl)-2-propenoate (321 mg, 1.652 mmol) and K2CO3 (228 mg, 1.652 mmol) in NMP (5 mL) was heated with a microwave reactor at 160° C. for 1.5 h. Purification via MDAP then afforded the title compound (120 mg, 22.25% yield). LCMS: rt=3.46 min, [M+H+]=539
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[CH3:25][O:26][C:27](=[O:32])[CH2:28][C:29](Cl)=[O:30]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[C:29](=[O:30])[CH2:28][C:27]([O:26][CH3:25])=[O:32])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)cn1NCc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)CC(=O)Cl
Product: COC(=O)CC(=O)N(Cc1ccc(-c2ccccc2)cc1)n1cc(Cl)cc1C(=O)OC

Procedure:
Prepared according to the acylation condition used in Example 2 step f) from 1-[(biphenyl-4-ylmethyl)-amino]-4-chloro-1H-pyrrole-2-carboxylic acid methyl ester and chlorocarbonyl-acetic acid methyl ester (1.5 eq.). ESI (m/z): 441 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([Cl:33])=[CH:7][C:8]([F:32])=[C:9]([CH:31]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23]CC3C=CC=CC=3)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)(=[O:3])[CH3:2]>CO.ClC(Cl)Cl.CN(C=O)C.[Pd]>[C:1]([O:4][C:5]1[C:6]([Cl:33])=[CH:7][C:8]([F:32])=[C:9]([CH:31]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(Nc3cc(OC(C)=O)c(Cl)cc3F)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1cc2c(Nc3cc(OC(C)=O)c(Cl)cc3F)ncnc2cc1O
Yield: 83.3 %

Procedure:
A solution of 4-(5-acetoxy-4-chloro-2-fluoroanilino)-7-benzyloxy-6-methoxyquinazoline (250 mg, 0.54 mmol) in methanol (5 ml), trichloromethane (5 ml) and DMF (1 ml) was stirred under hydrogen at 1 atmosphere with 5% palladium-on-charcoal catalyst (100 mg) for 4 hours. The catalyst was removed by filtration through diatomaceous earth and the solvent removed by evaporation. The residue was dissolved in ethyl acetate, washed with water and brine, and dried (MgSO4). Most of the solvent was removed by evaporation, the mixture was cooled and hexane added to obtain solid product which was collected by filtration, washed with hexane/ethyl acetate and dried to give 4-(5-acetoxy-4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (170 mg, 45%).
Reaction SMILES: [I:1][CH2:2][CH2:3][C@H:4]([OH:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:13][Si:14](Cl)([CH3:16])[CH3:15]>C(Cl)Cl>[I:1][CH2:2][CH2:3][C@H:4]([O:12][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCC[C@@H](O)CCI
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Product: CCCCCCC[C@H](CCI)O[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 1-iodo-3(R)-decanol (490 mg) in methylene chloride (10 ml) was added trimethylsilyl chloride (336 mg) and N-ethyldiiosopropylamin (398 mg). After stirring for 1 hour, the mixture was washed with phosphate buffer (pH 6.5, 0.066M, 10 ml) and brine (10 ml), dried and evaporated in vacuo. The residue was purified by chromatography (silica gel, 20 g, methylene chloride as eluent) to give the title compound as an oil, δ (300 MHz) 0.13 (9H, s), 0.87 (3H, t), 1.15-1.50 (12H, m), 1.92 (2H, m), 3.21 (2H, m) and 3.70 (1H, m).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].C(OC([N:12]1[CH2:17][C@@H:16]([CH2:18]OS(C2C=CC(C)=CC=2)(=O)=O)[C@H:15]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][O:37][CH2:38][C@H:39]([O:41][CH2:42][CH3:43])[CH3:40])=[CH:32][CH:31]=2)[C@@H:14]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][C:49]3[O:54][CH2:53][CH2:52][N:51]([CH2:55][CH2:56][CH2:57][O:58][CH3:59])[C:50]=3[CH:60]=2)[CH2:13]1)=O)(C)(C)C>CN1CCCN(C)C1=O.CC(OC)(C)C>[CH2:42]([O:41][C@H:39]([CH3:40])[CH2:38][O:37][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([C@@H:15]2[C@@H:14]([O:44][CH2:45][C:46]3[CH:47]=[CH:48][C:49]4[O:54][CH2:53][CH2:52][N:51]([CH2:55][CH2:56][CH2:57][O:58][CH3:59])[C:50]=4[CH:60]=3)[CH2:13][NH:12][CH2:17][C@H:16]2[CH2:18][NH2:1])=[CH:31][CH:32]=1)[CH3:43]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](COS(=O)(=O)c3ccc(C)cc3)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: COC(C)(C)C
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CN)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.57 mmol of sodium azide are added to a solution of 0.91 mmol of (3R,4R,5S)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-3-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (example 5d) in 5 ml of 1,3-dimethyl-tetrahydro-pyrimidin-2-one (DMPU) under argon at 50° C. After 2 h, the reaction mixture is cooled to RT, diluted with TBME, washed successively with H2O (2×) and brine, dried over Na2SO4 and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a pale yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.27 (EtOAc/heptane 1:1); Rt=5.98 (gradient I).
Reaction SMILES: [ClH:1].[CH:2]1[CH:11]=[CH:10][C:9]2[CH2:12][CH2:13][CH2:14][N:7]3[C:8]=2[C:3]=1[C@@H:4]1[CH2:18][NH:17][CH2:16][C@H:5]1[C:6]3=[O:15].C=O.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCCl.C(O)C.CCOCC>[ClH:1].[CH3:21][N:17]1[CH2:18][C@@H:4]2[C@H:5]([C:6](=[O:15])[N:7]3[CH2:14][CH2:13][CH2:12][C:9]4[CH:10]=[CH:11][CH:2]=[C:3]2[C:8]3=4)[CH2:16]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1[C@@H]2CNC[C@H]2c2cccc3c2N1CCC3
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCCl
Solvent: CCOCC
Product: CN1C[C@H]2C(=O)N3CCCc4cccc(c43)[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
To a solution of (±)-trans-5,6,9,10,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinolin-8(8aH)-one, hydrochloride salt from EXAMPLE 3 (200 mg, 0.76 mmol) in 5 mL of 1,2-dichloroethane was added 37% aqueous formaldehyde (0.065 mL, 0.76 mmol) and sodium triacetoxyborohydride (260 mg, 1.22 mmol). The resulting mixture was stirred at ambient temperature for 1 h and then the reaction was quenched with water. The mixture was partitioned between chloroform and saturated aqueous sodium carbonate. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo. A portion of the residue (50 mg, 0.21 mmol) was dissolved in 1 mL ethanol and 5 mL of ether and then there was added 2M HCl in ether (0.105 mL, 0.21 mmol). A solid precipitated out of solution. The solvents were decanted and the solid was triturated twice with ether and dried in vacuo to afford 25 mg (43%) of the title compound of EXAMPLE 5 as an off white powder. 1H NMR (d6-dmso): δ 7.12 (d, 1H, J=7.4 Hz), 6.99 (t, 1H, J=7.3 Hz), 6.97-6.90 (m, 1H), 4.25-4.12 (m, 2H), 3.75-3.65 (m, 2H), 3.40-3.20 (m, 3H), 2.97-2.90 (m, 3H), 22.81-2.70 (m, 3H), 1.88-1.80 (m, 2H). LRMS (ES)+: 243.4 (M+H)+.