Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CCOCC.CCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH:14]1([N:20]=[C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)C(=O)c1cccn1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCC
Solvent: CCOCC
Product: CCOC(=O)C(=NC1CCCCC1)c1cccn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a solution of 25 g ethyl 1-methylpyrrole-2-glyoxylate and 44.5 g cyclohexylamine in 700 ml ether under nitrogen at 0° C. is added 8.8 ml of titanium tetrachloride in 80 ml pentane. After stirring at room temperature overnight, the precipitate is removed by filtration. The filtrate is evaporated and the resulting oil distilled. The fraction collected at 111°-117° C. (5 millitorr) is crystallized from hexane to afford a 15% yield of ethyl α-cyclohexylimino-1-methylpyrrole-2-acetate, m.p. 35°-36° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][CH:7]=[C:8]([N+:17]([O-])=O)[C:9]=2[N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([C:4]2[C:9]([N:10]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]3)=[C:8]([NH2:17])[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CN1CCN(c2c(C3CC3)cncc2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2c(N)cncc2C2CC2)CC1

Procedure:
To a solution of 1-(3-cyclopropyl-5-nitro-4-pyridyl)-4-methyl-piperazine (220.4 mg, 0.8403 mmol) in methanol (25 mL) was added Pd on carbon (10%, Degussa, 6.387 mg, 0.006002 mmol). The reaction mixture was stirred at room temperature under a balloon of hydrogen, for 7 h. The reaction was filtered through a plug of Celite, washed with MeOH and the filtrate was concentrated in vacuo yielding 5-cyclopropyl-4-(4-methylpiperazin-1-yl)pyridin-3-amine as an orange residue. (194 mg, 99%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=O.OCC1C=CC(/[CH:20]=[CH:21]/[C:22]([O:24]C)=[O:23])=CC=1>>[CH3:20]/[C:21](=[CH:1]\[C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([CH2:6][OH:8])[CH:4]=1)/[C:22]([OH:24])=[O:23]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: COC(=O)/C=C/c1ccc(CO)cc1
Product: C/C(=C\c1cccc(CO)c1)C(=O)O

Procedure:
The title compound was prepared from 3-formylbenzoic acid by the same methodology used to make Intermediate A.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH:12][C:13]([O:15]C2C=CC([N+]([O-])=O)=CC=2)=O)=[CH:6][C:5]=1[C:25]([F:28])([F:27])[F:26].[NH2:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1>CN1C(=O)CCC1>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH:12][C:13]([NH:30][C:31]2[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=2)=[O:15])=[CH:6][C:5]=1[C:25]([F:26])([F:27])[F:28]
Reactant: COC(=O)c1cc(OC)c(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1C(F)(F)F
Reactant: Cc1cnc(N)cn1
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(OC)c(NC(=O)Nc2cnc(C)cn2)cc1C(F)(F)F
Temperature: 85 °C

Procedure:
To a stirred solution of 5-methoxy-4-(4-nitro-phenoxycarbonylamino)-2-trifluoromethyl-benzoic acid methyl ester (878 mg, 2.1 mmol) in 4.2 mL NMP at room temperature under nitrogen was added 2-amino-5-methylpyrazine (232 mg, 2.1 mmol) and the reaction heated to 85° C. After six hours the reaction was cooled to room temperature and a precipitate formed. The precipitate was triturated with EtOAc (25 mL) and the urea isolated by filtration as a tan solid (470 mg, 58%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1Cl.[CH:15]([NH2:18])([CH3:17])[CH3:16]>CS(C)=O>[CH:15]([NH:18][C:8]1[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[C:2]([F:14])([F:13])[F:1])([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)N
Solvent: CS(C)=O
Product: CC(C)Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 0 °C
Yield: 100.2 %

Procedure:
To a solution of 45 g of 3-(trifluoromethyl)-4-chloronitrobenzene in 150 ml of DMSO was added 13 g of isopropylamine. The mixture was heated at 80°-90° C. for two hours, poured over ice water, acidified and filtered. The filter cake was dried to yield 49.6 g of product; m.p. 35°-36° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([CH3:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.[Br:13]Br>Br.C(O)(=O)C>[BrH:13].[Br:13][CH2:9][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:12])=[CH:5][C:6]=1[CH3:11])=[O:10]
Reactant: CC(=O)c1c(C)cc(C)nc1C
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(C)c(C(=O)CBr)c(C)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2,4,6-trimethylpyridin-3-yl)ethanone (5.0 g, 30.6 mmol) in 33% HBr in acetic acid solution (10.2 mL) was added bromine (1.57 ml, 30.6 mmol) in acetic acid (10.2 mL) dropwisely. The reaction was stirred at 70° C. for 2.0 h. The solution was cooled to room temperature and washed with ether. The residue was dried under reduced pressure to give 2-bromo-1-(2,4,6-trimethylpyridin-3-yl)ethanone hydrobromide, which was used directly for the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44]N)=[CH:40][CH:39]=1>>[CH3:36][O:37][C:38]1[CH:39]=[C:40]2[C:41](=[CH:42][CH:43]=1)[NH:44][C:22]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=1)=[C:21]2[CH2:20][CH2:19][CH2:18][N:15]1[CH2:14][CH2:13][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:34])[CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH2:17][CH2:16]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Product: COc1ccc2[nH]c(-c3ccc(C(F)(F)F)cc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl)phenyl]pentyl}-4-piperidinyl)phenyl]propanamide and 4-methoxyphenylhydrazine hydrochloride: ESMS m/e: 578.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].C(N(CC)CC)C.Cl[C:40]([C:42]1[CH:43]=[C:44]([CH:49]=[CH:50][CH:51]=1)[C:45]([O:47][CH3:48])=[O:46])=[O:41]>ClCCl>[N:26]1([C:23]2[CH:24]=[CH:25][C:2]([NH:1][C:40]([C:42]3[CH:43]=[C:44]([CH:49]=[CH:50][CH:51]=3)[C:45]([O:47][CH3:48])=[O:46])=[O:41])=[C:3]([C:4](=[O:5])[NH:6][C:7]3[CH:11]=[CH:10][N:9]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=4)[N:8]=3)[CH:22]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 0 °C
Yield: 83.1 %

Procedure:
Into a 100-mL 3-necked round bottom flask, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide (260 mg, 0.61 mmol, 1.00 equiv) in dichloromethane (20 mL), and triethylamine (123 mg, 1.22 mmol, 2.01 equiv). This was followed by dropwise addition of a solution of methyl 3-(chlorocarbonyl)benzoate (144 mg, 0.73 mmol, 1.20 equiv) in dichloromethane (10 mL) with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature, with reaction progress monitored by LCMS. The resulting mixture was washed with 3×20 mL of water and 20 mL of brine, then dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to give 300 mg of crude product as a brown solid.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:32]([OH:34])=O)[CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[NH:24][C:25]([O:27][CH3:28])=[N:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.[O:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[NH:24][C:25]([O:27][CH3:28])=[N:26][C:22]=4[CH:21]=3)[C:32](=[O:34])[N:48]3[CH2:47][CH2:46][N:45]([CH:42]4[CH2:43][CH2:44][O:39][CH2:40][CH2:41]4)[CH2:50][CH2:49]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)O)cc(C)c2[nH]1
Product: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)N3CCN(C4CCOCC4)CC3)cc(C)c2[nH]1

Procedure:
Prepared analogously to Example 1h from 90 mg (0.16 mmol) (R)-1-carboxy-2-(2-methoxy-7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 40 mg (0.24 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[C:10](OCC)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CCCCCC>[OH:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:3][CH2:2][N:1]=[C:21]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: NCCNCCCCO
Reactant: CCCCCCCCCCCC(=O)OCC
Solvent: CCCCCC
Product: CCCCCCCCCCCC1=NCCN1CCCCO
Yield: 54.2 %

Procedure:
8 g (60.6 mmoles) of 4-(2-aminoethylamino)butanol and 12.5 g of ethyl dodecanoate were treated as under Example 25. The resulting 10.8 g of an oil (66.7%) was dissolved in 100 ml of hexane and kept in the freezer to give 8.8 g of pure product, m.p. 58°-60° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: OCCCCCCCl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCCCl)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A solution of 6-chloro-1-hexanol (100 g) in dry pyridine (500 ml) was treated with p-toluenesulfonyl chloride (227 g) at 5°-10° C. After stirring 2 h at 10° C., the mixture was poured into ice water (2 L), followed by extraction with ethyl ether. The organic extract was washed with ice water and brine, dried, filtered and evaporated to give a syrup, which was further dried at high vacuum. The crude product was overlayered with pentane and cooled in dry ice/acetone to give a solid (210 g, 99%), mp 36°-37° C.
Reaction SMILES: C1(C2C=CC([CH:8]=[O:9])=CC=2)CC1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([F:23])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[F:23][C:19]1([C:16]2[CH:17]=[CH:18][C:13]([CH:8]=[O:9])=[CH:14][CH:15]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: FC1(c2ccc(Br)cc2)CCC1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccc(C2(F)CCC2)cc1

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S1-A) using 1.64 g of 1-bromo-4-(1-fluoro-cyclobutyl)-benzene (7.16 mmol), 4.92 ml of a 1.6 molar solution of n-BuLi in hexane (7.87 mmol) and 1.1 ml of DMF (14.32 mmol). 4-(1-Fluoro-cyclobutyl)-benzaldehyde was isolated as crude product as a light yellow liquid (1.23 g, 96%). 1H NMR (CDCl3, 300 MHz): δ 1.84 (m, 1H), 2.15 (m, 1H), 2.49-2.81 (m, 5H), 7.63 (d, J=8 Hz, 2H), 7.92 (d, J=8 Hz, 2H), 10.03 (s, 1H).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O.Cl>C(O)(=O)C>[CH3:11][N:12]1[CH:13]=[CH:14][CH:15]([C:3]2[C:2]([OH:10])=[CH:9][C:7]([CH3:8])=[CH:6][C:4]=2[OH:5])[CH2:16][CH2:17]1
Reactant: CN1CCCCC1=O
Reactant: Cc1cc(O)cc(O)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(O)c(C2C=CN(C)CC2)c(O)c1
Yield: 30.1 %

Procedure:
Orcinol hydrate (15 g) and N-methylpiperidone (11.0 g) were dissolved in 30 ml acetic acid and treated with HCl gas as described in Example VI giving 6.42 g of product, m.p. 241°-243°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2[C:26](=[CH:27]C=CC=2)[C@@:25]2([C:43]3C(=CC4OCCOC=4[CH:42]=3)OC2)C1=O>>[CH2:27]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22])[CH2:26][CH2:25][CH2:43][CH3:42]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2[C@@]12COc1cc3c(cc12)OCCO3
Product: CCCCCN1C(=O)[C@]2(COc3cc4c(cc32)OCCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using (R)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, (R)-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (74%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.25-7.30 (m, 1H), 7.16-7.11 (m, 1H), 6.99-7.04 (m, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.47 (s, 1H), 6.19 (s, 1H), 4.73 (ABq, 2H), 4.20-4.06 (m, 4H), 3.86-3.59 (m, 2H), 1.82-1.63 (m, 2H), 1.42-1.28 (m, 4H), 0.89 (t, J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ177.2, 155.2, 144.5, 142.4, 138.2, 132.5, 128.7, 123.9, 123.0, 121.2, 111.4, 108.5, 99.3, 80.1, 64.5, 63.9, 58.0, 40.3, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 366.1 (M+1).
Reaction SMILES: [Cl:1][N:2]([C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].Br[CH2:24][CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][N:2]([C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:24][CH2:25][CH2:26][O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9]
Reactant: BrCCCOC1CCCCO1
Reactant: COc1cc2c(N(Cl)c3ccccc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(N(Cl)c3ccccc3F)ncnc2cc1OCCCOC1CCCCO1
Temperature: 90 °C
Yield: 48.7 %

Procedure:
A mixture of 4-(chloro-2-fluoroanilino)-7-hydroxy-6methoxyquinazoline (3.28 g, 10 mmol), (prepared as described for the starting material in Example 2), 1-bromo-3-tetrahydropyranyloxypropane (2.5 g, 11 mmol) and potassium carbonate (5.0 g, 36 mmol) in DMF (50 ml) was stirred and heated at 90° C. for 3 hours. The reaction mixture was allowed to cool, was diluted with water (500 ml) and extracted with ethyl acetate (3×100 ml). The extracts were combined, washed with water (×3), and then brine, and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by column chromatography eluting with ethyl acetate. The purified product was recrystallised from ethyl acetate/hexane to give 4-(chloro-2-fluoroanilino)-6-methoxy-7-(3-tetrahydropyran-2-yloxypropoxy)quinazoline (2.25 g, 49%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][C:8]([CH3:41])([CH3:40])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.Cl[C:43]1[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][N:44]=1>CN(C)C=O>[OH:7][C:8]([CH3:40])([CH3:41])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:20]=[CH:21][C:22]([C:43]3[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][N:44]=3)=[CH:23][CH:24]=2)[CH3:18])[CH2:12][CH2:11]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2ccc(C#N)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 105.2 %

Procedure:
2 M aqueous Na2CO3 solution (1.04 mL) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.50 g) and 6-chloro-nicotinonitrile (0.22 g) in dimethylformamide (3 mL). The resulting mixture was sparged with argon for 5 min, before [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (51 mg) is added. The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2->80:20) to afford (S)-6-(4-{(S)-1-[6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-nicotinonitrile as an oil (0.50 g) which was crystallized from a mixture of EtOAc (15 mL) and iPr2O (5 mL) by scratching to yield a solid, mp 160-162° C. Yield: 0.32 g (67% of theory). Mass spectrum (ESI+): m/z=456 [M+H]+. mp=160-162° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1Br)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[CH:42]([CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1)=[O:43]>C1COCC1>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:42]([OH:43])[CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])[CH2:46][CH2:45]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Br)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 42.5 %

Procedure:
To a solution of (3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine (115 mg, 0.21 mmol) in THF (0.5 mL) at 0° C. was added i-PrMgCl/LiCl (0.3 mL, 0.39 mmol). The mixture was stirred 0° C. for 3 hours and tert-butyl 4-formylpiperidine-1-carboxylate (70.7 mg, 0.33 mmol) in THF (0.1 mL) was added. The mixture was stirred at 0° C. to room temperature for 3 hours and quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+S Biotage silica column (eluted with 0-50% ethyl acetate in hexanes) to afford the title compound (62.2 mg, 44%). 1H NMR (400 MHz, CDCl3) δ ppm 1.12-1.19 (m, 1H) 1.20-1.32 (m, 1H) 1.43 (s, 9H) 1.69-1.78 (m, 1H) 1.89 (dd, J=13.07, 1.87 Hz, 1H) 2.46-2.67 (m, 2H) 3.99-4.15 (m, 2H) 4.18 (s, 3H) 4.66-4.73 (m, 2H) 4.68-4.83 (m, 4H) 4.87 (d, J=15.77 Hz, 1H) 7.33 (s, 1H) 7.55 (s, 2H) 7.64 (s, 2H) 7.77 (s, 1H). MS (ES+) Calc: 696.2, Found: 697.6 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[N:9]2)=[N:6][CH:7]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[N:9]2)=[N:6][CH:7]=1
Reactant: OCc1ccn(-c2ccc(F)cn2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccn(-c2ccc(F)cn2)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a suspension of [1-(5-fluoropyridin-2-yl)-1H-pyrazol-3-yl]methanol obtained in Reference Example 28 (8.0 g, 34.0 mmol) in CHCl3 (100 mL), 85% manganese dioxide (29.6 g, 0.34 mol) was added, and the resulting mixture was stirred for 3 hours at 60° C. The reaction mixture was filtered through Celite®, the solid was washed with CHCl3, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with diethyl ether, and filtered out to obtain the title compound (5.3 g) (light brown solid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@H:19]5[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][C@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].N>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3ccc(Cl)c(Cl)c3)cc3c1N2CCC3
Agent: N
Product: Clc1ccc(-c2cc3c4c(c2)[C@H]2CNCC[C@H]2N4CCC3)cc1Cl
Yield: 101 %

Procedure:
The title compound (72.6 mg, 100%) was prepared by the method of Example 112 from tert-butyl (±)-cis-2-(3,4-dichlorophenyl)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (90 mg, 0.20 mmol) as pale yellow amorphous solid. 1H NMR (CDCl3, 300 MHz) δ7.58 (d, 1H, J=2.2 Hz), 7.41 (d, 1 H, J=8.4 Hz), 7.32 (dd, 1H, J=2.2, 8.4 Hz), 7.09 (s, 1H), 7.07 (s, 1H), 3.34-3.46 (m, 1H), 3.31 (dt, 1H, J=4.4, 10.7 Hz), 3.03-3.13 (m, 2H), 2.83-2.92 (m, 2H), 2.61-2.78 (m, 4H), 2.10-2.19 (m, 2H), 1.74-1.91 (m, 2H) ppm. MS (CI, NH3): 359 (base, M+H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[C:9]([CH3:18])([CH3:17])[CH2:8][CH2:7]1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(OCC)(=O)C.C(Cl)Cl>[CH3:16][C:12]1[C:13]([C:1](=[O:3])[CH3:2])=[CH:14][C:15]2[C:6]([CH3:19])([CH3:5])[CH2:7][CH2:8][C:9]([CH3:18])([CH3:17])[C:10]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a 250 ml three-necked round bottomed flask fitted with a magnetic stirring bar and a reflux condenser containing acetyl chloride (2.3 g, 29.7 mmol) and 50 ml of DCM was added 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene 1b (5 g, 24.8 mmol) followed by slow addition (ca. 0.5 g portions) of AlCl3 (7.5 g, 56.2 mmol). The brown mixture was stirred for 30 min and then heated at reflux for 15 min. Additional AlCl3 (1-2 g) was necessary to effect the completion of the reaction. The cooled reaction mixture was poured into 200 ml of vigorously stirred ice water followed by acidification with 20% aqueous hydrochloric acid 50 ml and addition of 100 ml of ethyl acetate. Stirring was continued until the organic layer was yellow 15 min. The organic layer was extracted with ethyl acetate (2×100 ml), dried over MgSO4, filtered and concentrated in vacuo. Kugelrohr distillation (80-120° C., 3×10−4 torr) gave an analytically pure sample of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-yl)ethanone 5.31 g (88%) as a white solid; m.p. 54-56° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]2[C:3]=1[CH:12]=[CH:13][NH:9]2
Reactant: C=C[Mg]Br
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: Cc1ccc(Br)c2cc[nH]c12
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 35.3 %

Procedure:
To a solution of 4-bromo-2-nitrotoluene (3.0 g, 13.9 mmol) in THF (40 mL) at −40° C. was added vinyl magnesium bromide (48.6 mmol, 48.6 mL; 1.0 M in THF) dropwise over 15 minutes and the mixture stirred at −40° C. for 1.5 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, separated and dried (MgSO4). The residue was evaporated and purified by column chromatography to yield 4-bromo-7-methylindole (1.03 g).