Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]2[CH2:21][NH:20][CH2:19][CH:18]2[N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27]([F:35])[CH:26]=2)[CH3:23])[CH:13]=[CH:14][C:15]=1[Cl:16].C(N(CC)CC)C>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:20]1[CH2:19][CH:18]([N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[C:27]([F:35])[CH:26]=2)[CH3:23])[CH:17]([C:12]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=2)[CH2:21]1)=[O:7]
Reactant: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)CCCCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(C(=O)CCCCBr)CC1c1ccc(Cl)c(Cl)c1
Yield: 83.4 %

Procedure:
To a stirred solution of 5-bromo-pentanoyl chloride (0.167 ml, 1.25 mmol) in THF (10 ml) at RT was added over 1 hour a solution of [(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-(3-fluoro-4-trifluoromethyl-benzyl)-methyl-amine (Intermediate VIII-1, 0.50 g, 1.19 mmol) and triethyl amine (0.18 ml, 1.30 mmol) in THF (5 mL). The reaction was stirred over night, quenched by addition of an aqueous solution of NaHCO3, and the product extracted with EtOAC. Purification by flash chromatography (SiO2, EtOAc/Hx 1:1) yielded 0.58 g (83%) of the title compound as a white solid. ES-MS m/e: 584.4 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].[CH2:11](O)[CH2:12][OH:13].CO>ClCCl.C1C(=O)N(Br)C(=O)C1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2([CH3:1])[O:13][CH2:12][CH2:11][O:3]2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: OCCO
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CO
Product: CC1(c2ccc(Cl)cc2)OCCO1
Temperature: 25 °C
Reaction time: 70 h
Yield: 55.4 %

Procedure:
To a stirred mixture of 4-chloroacetophenone (1.3 mL, 10 mmol), triethylformate (2.0 mL, 12 mmol), ethylene glycol (1.7 mL, 30 mmol) and dry methanol (1.2 mL) in dry dichloromethane (50 mL) was added NBS (53 mg, 0.30 mmol). The mixture was protected from light and stirred at room temperature under an inert atmosphere of nitrogen for 70 h. After the mixture was washed with saturated sodium bicarbonate solution (20 mL), the aqueous phase was extracted with dichloromethane (3×30 mL). The combined organic solution was washed with water (2×20 mL), brine (1×20 mL), then dried (Na2SO4) and concentrated under reduced pressure. Flash column chromatography of the residue, eluting with 37% aqueous ammonia:ether:hexane (0.02:1:6) afforded 2-(4-chlorophenyl)-2-methyl-1,3-dioxolane (21) as a colourless oil (1.1 g, 51%). 1H nmr (300 MHz, CDCl3) 1.63 (s, 3H, CH3), 3.72-3.82 (m, 2H, OCH2), 3.98-4.09 (m, 2H, OCH2), 7.42 (d, J=8.6 Hz, 2H, 2×ArH), 7.30 (d, J=8.6 Hz, 2H, 2×ArH).
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[S:25][C:26]2[CH2:32][CH2:31][CH2:30][CH2:29][C:27]=2[CH:28]=1)[C:20]([O:22][CH3:23])=[O:21].C(NC(C1SC2CCCCC=2C=1)C(O)=O)(OC(C)(C)C)=O>>[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[S:25][C:26]3[CH2:32][CH2:31][CH2:30][CH2:29][C:27]=3[CH:28]=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: COC(=O)C(N)c1cc2c(s1)CCCC2
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CC(C)(C)OC(=O)NC(C(=O)O)c1cc2c(s1)CCCC2
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cc2c(s1)CCCC2

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetate (prepared from N-Boc-2-amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetic acid [CAS 95361-97-0] using General Procedures G above and the Boc removal procedure described in Example D3 above), the title compound was prepared as a solid. The product was purified by tituration using Et2O/hexanes.
Reaction SMILES: [Li+].[BH4-].C[O:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([Br:15])[CH:8]=1.O>C1COCC1>[Br:15][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][OH:4])[CH:12]=[CH:11][C:10]=1[C:13]#[N:14]
Reactant: COC(=O)Cc1ccc(C#N)c(Br)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CCO)cc1Br
Reaction time: 12 h

Procedure:
LiBH4 (1.48 mL, 2.95 mmol, 2 M in THF) was added to a stirred solution of methyl(3-bromo-4-cyanophenyl)acetate (0.50 g, 2.0 mmol) in THF (25 ml) at 0° C. The resulting solution was stirred for 12 h. Water (15 ml) was added, and the resulting solution was extracted with dichloromethane (2×50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure to yield the crude product as a cloudy oil. 1H NMR (500 MHz, CDCl3) δ 7.63 (s, 1H), 7.61 (d, J=5.7, 1H), 7.33 (d, J=7.8 Hz, 1H), 3.93 (t, J=1.6, J=4.8 Hz, 2H), 2.92 (t, J=6.6, J=5.1 Hz, 2H). LC-MS (IE, m/z): 210.1 [(M+1)]+−OH].
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:24]([OH:26])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([O:34][C:35](=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH2:42])[C:37]=1[CH3:43])C1C=CC=CC=1>>[C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:15][C:14]=3[C:24]([NH:42][C:38]3[C:37]([CH3:43])=[C:36]([CH:41]=[CH:40][CH:39]=3)[C:35]([OH:44])=[O:34])=[O:26])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Reactant: Cc1c(N)cccc1C(=O)OCc1ccccc1
Product: Cc1c(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)cccc1C(=O)O

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) was reacted with 3-amino-2-methyl-benzoic acid benzyl ester (prepared in two steps from 2-methyl-3-nitro-benzoic acid) according to the procedure of Example 20, step d. The benzyl ester was hydrogenated using the same procedure as in Example 1, step c to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 13.00 (1H, br s), 11.95 (1H, br s), 9.31 (1H, br s), 8.01 (1H, d), 7.49 (1H, d), 7.24 (1H, m), 2.85 (2H, m), 2.60 (1H, m), 2.39 (3H, s), 1.93-1.24 (27H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 62.84; H, 8.55; N, 7.80%. C37H56N4O8.1.0 mol H2O requires: C, 63.23; H, 8.32; N, 7.97%.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(OCC)(=O)C>CN(C=O)C>[CH3:32][C:31]([CH3:34])([CH3:33])[CH2:30][CH2:29][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1
Reactant: CC(C)(C)CCBr
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)CCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 70 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromo-3,3-dimethylbutane (0.183 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 368.2 (M+H)+, HRMS calcd for C22H30N3O2 368.2338 (M+H)+, found 368.2321, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=11.1 min, 96.8% purity.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15].CCCCCCC>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH:15][C:8]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:10])=[O:9]
Reactant: NCc1ccccc1F
Reactant: Cc1ccccc1N=C=O
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: Cc1ccccc1NC(=O)NCc1ccccc1F

Procedure:
ortho-Tolylisocyanate (4.95 ml) was added to a solution of 2-fluorobenzylamine (4.56 ml) in toluene (50 ml) under an atmosphere of nitrogen at 5° C. to produce rapid formation of a white solid. Heptane was added, the solid broken up and filtered off to afford 1-(2-fluorobenzyl)-3-(2-methylphenyl)urea (9.5 g) as a white solid. The urea (8 g) and cyanoacetic acid (2.9 g) were ground together and heated in acetic anhydride (15 ml) to 80° C. After cooling the reaction mixture to room temperature, diethyl ether was added and washed with water. The separated ether phase was dried over magnesium sulphate, filtered and evaporated in vacuo to give a crude solid residue (8.9 g). This residue was redissolved in dichloromethane (120 ml), triethylamine (5.7 ml) added and the mixture stirred at room temperature for 3 days. Filtration of the precipitate yielded the desired uracil as a white solid (2.6 g).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH:8]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH2:9]3)=[CH:4][C:3]=2[O:2]1.Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH:8]([N:14]4[CH2:19][CH2:18][N:17]([C:21]5[N:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[CH2:16][CH2:15]4)[CH2:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: Clc1ncccn1
Reactant: c1c2c(cc3c1OCO3)CC(N1CCNCC1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(N2CCN(C3CCc4cc5c(cc4C3)OCO5)CC2)nc1
Yield: 59.2 %

Procedure:
A solution of 2.6 g of 1-(6,7-methylenedioxy-1,2,3,4-tetrahydro-2-naphthyl) piperazine, 1.5 g of 2-chloropyrimidine and 1.4 g of potassium carbonate in 50 ml of anhydrous dimethylformamide, was heated at 130° C. for 3 hours. Then the reactional mixture was cooled, the so-formed salt was filtered out and the solvent was evaporated under reduced pressure. The so-obtained residue was taken up with 30 ml of a normal solution of methanesulphonic acid and 15 ml of chloroform. The mixture was decanted off, and the acid solution was alkalized with potassium carbonate. The base was extracted with chloroform. The solution was dried and the solvent was evaporated. There were obtained 3 g of crude product which recrystallized in 40 ml of ethanol gave 2 g of 1-(6,7-methylenedioxy-1,2,3,4-tetrahydro-2-naphthyl)-4-(2pyrimidinyl) piperazine, beige crystals melting at 134°-135° C. The corresponding monomethanesulfonate melts at 218°-225° C.
Reaction SMILES: [C:1]1([OH:8])[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.I[CH:10]([CH3:12])[CH3:11].[OH-].[K+].[OH-].[Na+]>C(O)C.O>[CH3:11][CH:10]([O:7][C:3]1[CH:2]=[C:1]([OH:8])[CH:6]=[CH:5][CH:4]=1)[CH3:12]
Reactant: Oc1cccc(O)c1
Reactant: CC(C)I
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Oc1cccc(O)c1
Yield: 19.5 %

Procedure:
To a solution of 1,3-benzenediol (8 g, 72.7 mmol) and 2-iodopropane (12 g, 70.6 mmol) in ethanol (100 mL preheated at reflux) was added a solution of KOH (83%, 5.3 g, 77.6 mmol) in water (20 mL) over a period of 30 minutes. The mixture was refluxed for 3 hours and poured into NaOH (1 N, 100 mL). The resulting mixture was extracted with ethyl acetate (3 times 50 mL) and the aqueous layer was acidified with 10% HCl to adjust the pH=5 and extracted with ethyl acetate (3 times 50 mL). The combined extracts were washed with brine (50 mL), dried and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE:EtOAc=5:1) to afford the title compound as a colourless oil (2.1 g).
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[I:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br>CN(C)C=O.C(OCC)(=O)C>[I:20][C:21]1[CH:22]=[C:23]([CH2:24][N:6]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:26]=[CH:27][CH:28]=1
Reactant: CCS(=O)(=O)NCc1cccnc1
Reactant: BrCc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(Cc1cccnc1)Cc1cccc(I)c1

Procedure:
A solution of N-(ethylsulfonyl)pyrid-3-ylmethylamine (1.1 g, 5.5 mmol), cesium carbonate (1.79 g, 5.5 mmol), and 3-iodobenzyl bromide (1.64 g, 5.5 mmol) was stirred in N,N-dimethylformamide (25 ml) for 5 h at room temperature. The mixture was diluted with ethyl acetate (100 ml) and washed four times with water (50 ml). The organics were separated, dried over sodium sulfate, filtered, and concentrated in vacuo to a crude residue. The residue was purified by radial chromatography on a 4 micron silica plate eluting with 3% methanol/dichloromethane to afford the title compound. 1H NMR: 8.6 (d,1H,J=4 Hz), 8.41 (s,1H), 7.75 (m,1H), 7.65 (m,1H), 7.60 (s,1H), 7.25-7.40 (m,2H), 7.08 (m,1H), 4.43 (s,2H), 4.33 (s,2H), 3.08 (q,2H,J=8 Hz), 1.43 (t,3H,J=8 Hz). MS calcd. 416.3; MS (M+1) 417.1.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)[CH3:14])[CH:3]=1.CNCCNC.[I-:27].[Na+]>O1CCOCC1.C(Cl)Cl.[Cu]I>[I:27][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)[CH3:14])[CH:3]=1
Reactant: C[C@@H](Oc1cc(Br)cc2ncccc12)[C@H]1CNC(=O)C1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(I)cc2ncccc12)[C@H]1CNC(=O)C1
Temperature: 110 °C
Yield: 26.3 %

Procedure:
50 mg of Example 27 and 9 mg of copper (I) iodide were suspended in 300 μL dioxane under argon. 9.6 μL N,N′dimethylethylendiamine and 45 mg of sodium iodide were added and the mixture heated to 110° C. over weekend. The mixture was diluted with DCM and extracted with aqueous ammonia and water, the organic phase was subsequently concentrated in vacuo and the residual purified with HPLC (XbridgeC18; MeOH/water, TFA) to yield 15 mg yellow solid as Example 37.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:10][CH2:11][NH2:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][O:26][CH2:27][C:28](Cl)=[O:29]>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:10][CH2:11][NH:12][C:28](=[O:29])[CH2:27][O:26][CH3:25])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(CCN)cc1OC1CCCC1
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)NCCc1ccc(OC)c(OC2CCCC2)c1
Reaction time: 0.25 h
Yield: 38.3 %

Procedure:
A solution of 3-cyclopentyloxy-4-methoxyphenethylamine (0.2 g, 0.85 mmol) in tetrahydrofuran (6 mL) was cooled to 0° C. and was treated with triethylamine (0.13 mL, 0.92 mmol) and methoxyacetyl chloride (0.078 mL, 0.85 mmol). The reaction was stirred under an argon atmosphere for 0.25 h, then was partitioned between methylene chloride and water. The extract was dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting with 5% methanol/chloroform, provided an oil; additional 0.1 g of impure product also obtained).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=O)=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>ClCCl.C(O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:12](=[O:14])/[CH:11]=[CH:10]/[C:7]3[CH:6]=[CH:5][C:4]([CH:3]([O:2][CH3:1])[O:15][CH3:16])=[CH:9][CH:8]=3)=[CH:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: COC(OC)c1ccc(/C=C/C(=O)O)cc1
Solvent: CCO
Solvent: ClCCl
Product: COC(OC)c1ccc(/C=C/C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1

Procedure:
Prepared analogously to Example 3.1.e. from (E)-3-(4-dimethoxymethylphenyl)acrylic acid and 4′-chlorobiphenyl-4-ylamine. Yield: 9.8 g, C24H22ClNO3 (M=407.90); calc.: molecular ion peak (M+H)+: 408/410; found: molecular ion peak (M+H)+: 408/410; Rf value: 0.3 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18](C1C=CC=C2C=1C(C#N)=CN2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]
Reactant: COc1ccc(Br)c2cn[nH]c12
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ncc12

Procedure:
Compound CXCVII was prepared from 4-Bromo-7-methoxy-1H-indazole using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10](C(=O)C(F)(F)F)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[K+]>CO>[C:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(C1NCC(c2ccccc2)c2ccccc21)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: c1ccc(C2CNCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 113.8 %

Procedure:
To a solution of 55 (0.9 g, 2.94 mmol) in MeOH (10 mL) were added water (2 mL), KOH (0.33 g, 5.89 mmol), and the reaction was stirred at room temperature for 12 hours. The mixture was washed with a saturated sodium chloride solution and extracted with 7:3 CH2Cl2/MeOH (3×10 mL). The combined organic layers were dried (K2CO3) and concentrated under reduced pressure to give 56 (0.70 g.˜100%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[C:15]([S:20][CH3:21])[N:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.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>[Cl:12][C:13]1[CH:18]=[C:17]([C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:16]=[C:15]([S:20][CH3:21])[N:14]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CSc1nc(Cl)cc(Cl)n1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cc(Cl)nc(SC)n2)cn1
Reaction time: 3 h

Procedure:
A mixture of 2-methoxy-5-pyridyl-boronic acid (600 mg, 2.04 mmol, Intermediate (37), prepared according to the procedure described in J. Org. Chem., 67, 7541, 2002), 4,6-dichloro-2-methylsulfanyl-pyrimidine [700 mg, 3.59 mmol, Intermediate (29)], and Cs2CO3 (2.9 g, 8.97 mmol) in ethylene glycol dimethyl ether (8 mL) and water (2 mL) is degassed by bubbling with Argon gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium(0) (207 mg, 0.18 mmol) at room temperature. After 3 hours at 85° C., the mixture is diluted with water (50 mL), and extracted twice with EtOAc (50 mL). The extracts are dried over magnesium sulfate, filtered, and concentrated to afford 4-chloro-6-(6-methoxy-pyridin-3-yl)-2-methylsulfanyl-pyrimidine [1.1 g, Intermediate (38)] as an oil. LCMS: RT=3.72 minutes, MS: 268 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:9][N:8]2[C:10]3[CH:11]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:13]=[CH:14][C:15]=3[C:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:7]2[C:6]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:5]=2[O:4][CH2:3]1.C(OC)(OC)OC.[CH:39](=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[BH3-]C#N.[Na+]>>[CH2:39]([NH:1][C@@H:2]1[CH2:9][N:8]2[C:10]3[CH:11]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:13]=[CH:14][C:15]=3[C:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:7]2[C:6]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:5]=2[O:4][CH2:3]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N)COc1cc(F)ccc1-3
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](NCc1ccccc1)COc1cc(F)ccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (7R)-7-amino-14-cyclohexyl-3-fluoro-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (Example 11, Step 5) was dissolved in HC(OMe)3 (50 eq) and a solution of benzaldehyde (1.1 eq) in HC(OMe)3 (50 eq) was added. The mixture was stirred overnight at RT to allow formation of the imine. All volatiles were evaporated and the residual material was dissolved in MeOH/HOAc (0.05 M). NaCNBH3 (1.1 eq) was added and the mixture was stirred at RT for 1 h. The solution was used directly in the next step. (ES+) m/z 513 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]=[CH:9]N(C)C)=[CH:4][CH:3]=1.[Na+].[I-].Cl[CH2:16][C:17](=[O:19])[CH3:18]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]([C:17](=[O:19])[CH3:18])=[CH:9][N:8]=2)[N:7]=1
Reactant: CC(=O)CCl
Reactant: CN(C)C=Nc1ccc(Cl)nn1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cnc2ccc(Cl)nn12
Temperature: 80 °C
Yield: 51.1 %

Procedure:
To a solution of N′-(6-chloro-pyridazin-3-yl)-N,N-dimethyl-formamidine (1.3 g, 7 mmol) in DMF (60 mL) was added NaI (1 g, 6.7 mmol) and chloroacetone (1 mL, 12.6 mmol). The mixture was heated at 80° C. overnight and concentrated under reduced pressure. The residue was purified by column chromatography to afford 1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethanone (0.7 g) in 51% yield. 1H-NMR (400 MHz, CDCl3) δ ppm 8.42 (s, 1H), 8.05 (d, 1H), 7.31 (d, 1H), 2.77 (s, 3H).
Reaction SMILES: O[CH:2]1[CH2:9][CH2:8][CH:7]([OH:10])[CH:6]2[N:11]([CH3:12])[CH:3]1[CH2:4][CH2:5]2.[C:13]([C:17]1[CH:18]=[C:19]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])([CH3:16])([CH3:15])[CH3:14]>C1(C)C(C)=CC=CC=1.CCOCC.[Ti]>[C:13]([C:17]1[CH:18]=[C:19]([CH2:28][CH2:29][C:30]([O:32][CH:3]2[CH2:4][CH2:5][CH:6]3[N:11]([CH3:12])[CH:2]2[CH2:9][CH2:8][CH:7]3[O:10][C:30](=[O:31])[CH2:29][CH2:28][C:19]2[CH:20]=[C:21]([C:24]([CH3:25])([CH3:27])[CH3:26])[C:22]([OH:23])=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:18]=2)=[O:31])[CH:20]=[C:21]([C:24]([CH3:25])([CH3:26])[CH3:27])[C:22]=1[OH:23])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Reactant: CN1C2CCC1C(O)CCC2O
Agent: [Ti]
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: CN1C2CCC(OC(=O)CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C1CCC2OC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 56.6 %

Procedure:
In a nitrogen atmosphere a stirred mixture of the diol mixture 2,6-dihydroxy-9-methyl-9-azabicyclo[3.3.1]nonane and 2,5-dihydroxy-9-methyl-9-azabicyclo[4.2.1]nonane (4.28 g., 0.025 mole), 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid (15.3 g, 0.055 mole) and 0.7 ml of titanium tetraisopripylate in 100 ml of xylene was heated under reflux in a flask equipped with a Dean-Stark trap for 14 hours. The xylene was evaporated under reduced pressure and the residue thus obtained was dissolved in ether. The ether solution was washed with 5% aqueous sodium hydroxide and then water. The dried (Na2SO4) solution was evaporated under reduced pressure to give an oily residue which was crystallized from petroleum ether. Recrystallization from methanol gave 9.8 g (56.6%) of the title ester, m.p. 107°-109°.