Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.C(N(CC)CC)C.Cl.[CH2:21]([NH2:30])/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:30][CH2:21]/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: NC/C=C/c1ccccc1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1csc2c(NC/C=C/c3ccccc3)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To 10 ml of a solution of 438 mg (2.0 mmol) of 2,4-dichloro-7-metylthieno[3,2-d]pyrimidine and 445 mg (4.4 mmol) of triethylamine in DMF was added 339 mg (2.0 mmol) of trans-cinnamylamine hydrochloride under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 2 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 341 mg (yield: 54.0%) of the title compound.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[CH:19])[CH:13]=1.N>>[Cl:11][C:12]1[CH:13]=[C:14]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[N:8][CH:7]=[CH:6][N:5]=3)[CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: ON=C(Cl)c1cnccn1
Agent: N
Product: Clc1cccc(-c2cc(-c3cnccn3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 1-chloro-3-ethynylbenzene (Apollo, 68 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ7.49 (s, 1H), 7.51-7.59 (m, 2 H), 7.85-7.91 (m, 1H), 7.94-8.04 (m, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.76 (dd, J=2.5, 1.5 Hz, 1H), 9.30 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 258 (M+H)+, 260 (M+H)+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[NH2:16][C:17]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].O>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:17]2[N:16]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:20][C:19](=[O:21])[C:18]=2[CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1oc(-c2ccccc2)nc2ccc(Cl)cc12
Reaction time: 16 h
Yield: 92.7 %

Procedure:
Benzoyl chloride (5.3 mL, 45 mmol) was added dropwise to a suspension of Na2CO3 (3.8 g, 36 mmol) and 2-amino-5-chloro-benzoic acid (3.1 g, 18 mmol) in THF (60 mL). The mixture was allowed to stir for 16 h and then H2O (200 mL) was added. The resulting precipitate was collected by filtration, washed with MeOH/H2O (1/1, 100 mL) and then dried in vacuo to provide 6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one (4.3 g, 92%). To a suspension of the benzoxazinone (5.0 g, 19 mmol) in CH2Cl2 (100 mL) at −78° C. was added o-tolylmagnesium chloride (2 M in THF, 48 mmol) dropwise. The mixture was allowed to warm to −30° C. and stir for 1 h. 1N HCl (100 mL) was then added. The organic phase was collected and the aqueous phase was washed with CH2Cl2 (2×50 mL). The combined organic portions were washed with 0.1N NaOH (2×50 mL), dried over MgSO4, filtered and concentrated in vacuo to provide N-[4-chloro-2-(2-methyl-benzoyl)-phenyl]-benzamide (6.3 g, 93%). The acylated amino-benzophenone (3.5 g, 10 mmol) was dissolved in MeOH (50 mL) containing KOH (3 M, 30 mmol) and was refluxed for 16 h. The solution was then cooled to room temperature and diluted with H2O (50 mL) and EtOAc (100 mL). The organic phase was collected, washed with 120 (3×50 mL), dried over MgSO4, filtered and evaporated to dryness in vacuo to provide 1m (2.4 g, 98%) MS m/z=246 (M+H).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C([O-])(O)=O.[Na+].[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>O1CCOCC1.O>[C:16]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reaction time: 8 h
Yield: 86.7 %

Procedure:
4-piperidone monohydrate hydrochloride (250 g, 1.62 mole) was dissolved in dioxane (1.5 L) and water (0.5 L). 217 g of NaHCO3 was added at 0° C. followed by slow addition of (BOC)2O (459 g, 2.1 mole). Reaction mixture was stirred for overnight. Solution was concentrated; residue was taken in water and extracted with ethyl acetate, washed with water and dried over anhydrous Na2SO4. Solvent was evaporated and product obtained was washed with hexane to get N-boc 4-piperidone (280 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[OH:18][C@H:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:2]2[N:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([OH:18])[CH2:20]1
Reactant: O[C@H]1CCCNC1
Reactant: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2ccc(I)cc2c(N2CCC[C@H](O)C2)c1S(C)(=O)=O
Yield: 54.4 %

Procedure:
4-Chloro-6-iodo-3-methanesulfonyl-2-methyl-quinoline (compound of example D.2) (300 mg, 0.786 mmol), (S)-(+)-3-hydroxypiperidine (119 mg, 0.865 mmol) and N,N-diisopropyl ethyl amine (0.148 mL, 0.865 mmol) were heated in dry N,N-dimethylformamide (3 mL) for 0.5 h at 100° C. N,N-Dimethylformamide was evaporated at 40° C./0.1 mbar, the residue was extraced with dichloromethane and 10% Na2CO3, and then purified by chromatography on silica gel in dichloromethane/methanol 20:1. One obtained a yellow oil which was triturated with ethyl acetate, and the resulting white crystals were filtered off. One obtained 191 mg (54%) of white crystals. MS: m/z=447 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH3:25][C:26]1([CH3:33])[O:30][CH:29]([CH2:31][NH2:32])[CH2:28][O:27]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([CH2:21][NH:32][CH2:31][CH:29]4[CH2:28][O:27][C:26]([CH3:33])([CH3:25])[O:30]4)=[CH:23][CH:24]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC1(C)OCC(CN)O1
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(C=O)cc3)n2)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(CNCC4COC(C)(C)O4)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.3 %

Procedure:
4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzaldehyde (150 mg, 0.438 mmol), (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (0.057 mL, 0.438 mmol), methanol (4 mL), and acetic acid (0.125 mL, 2.188 mmol) were loaded into a 25 mL flask equipped with a stirring bar. The mixture was stirred for about 10 minutes at room temperature under nitrogen. Sodium cyanoborohydride (27.5 mg, 0.438 mmol) was added in one portion, and the reaction mixture was stirred at room temperature overnight. Solvent was removed under reduced pressure and crude material was purified by RP-HPLC (A=50 mM ammonium acetate, B=ACN; 40% to 80% B over 30 min at 21.0 mL/min; UV λ=254 nm; Thermo Hyperprep HS C18, 8 μm, 250×21.2 mm column). Fractions containing product were combined, rotovapped and lyophilized to give N-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzyl)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (130.9 mg, 64.7%) as a white solid. LCMS (Table 1, Method c) Rt=2.59 min, m/z 458.62 (M+H)+; 1H NMR (400 MHz, DMSO) δ ppm 8.13 (d, 2H), 8.06 (d, 1H), 8.00 (dd, 1H), 7.61 (d, 2H), 7.39 (d, 1H), 4.82 (sept, 1H), 4.15 (p, 1H), 3.99 (dd, 1H), 3.84 (s, 2H), 3.63 (dd, 1H), 2.61 (ddd, 2H), 1.86 (s, 4H), 1.35 (d, 6H) 1.26 (s, 3H).
Reaction SMILES: C([O:8][C:9](=[O:58])[C@H:10]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[NH:11][C:12](=[O:50])[CH2:13][CH:14]([O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:48])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45](=[O:47])[CH3:46])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])C1C=CC=CC=1>O1CCCC1.CO.[Pd]>[C:45]([NH:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][C:38]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][C:31]([O:30][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:13][C:12]([NH:11][C@H:10]([C:9]([OH:58])=[O:8])[CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:50])=[O:49])=[O:48])(=[O:47])[CH3:46]
Reactant: CCCCCCCCCCCCCCCC(CC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OC(=O)CCCCCNC(=O)CCCCCNC(C)=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCCCCC(CC(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC(=O)CCCCCNC(=O)CCCCCNC(C)=O
Yield: 76.8 %

Procedure:
1.80 g of the above ester compound was treated with 8 ml of TFA to convert the ester to free carboxylic acid and after adding thereto 5 ml of methylenechloride, 1.20 g of L-phenylalanine benzyl ester TsOH salt, 0.4 ml of TEA and 590 mg of DCC, the mixture was trated in the same manner as in Example 14-(ii) to provide 740 mg of N-[3-[6-(6-acetamidohexanamido)hexanoyloxy]octadecanoyl]-L-phenylalanine benzyl ester. 660 mg of the ester compound thus were dissolved in a mixture of 30 ml of tetrahydrofuran and 15 ml of methanol and after carrying out catalytic reduction by using 100 mg of 10% Pd-C and treating in the same manner as in Example 23-(iv), 450 mg of N-[3-[6-(6-acetamidohexanamido)hexanoyloxy]octadecanoyl]-L-phenylalanine was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][C:13]3[N:17]4[N:18]=[C:19]([C:22]([O:24]CC)=O)[CH:20]=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:27][CH3:28]>C1COCC1>[CH3:28][NH:27][C:22]([C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([CH2:12][C:10]3[CH:9]=[CH:8][C:6]4[N:7]=[C:3]([S:2][CH3:1])[S:4][C:5]=4[CH:11]=3)=[CH:14][N:15]=2)[N:18]=1)=[O:24]
Reactant: CCOC(=O)c1ccc2ncc(Cc3ccc4nc(SC)sc4c3)n2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2ncc(Cc3ccc4nc(SC)sc4c3)n2n1

Procedure:
Ethyl 3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carboxylate (115 mg, 0.3 mmol) was heated with 2 mL of 2.0 M NH2Me in THF at 85° C. in a sealed tube for 1 h, at 100° C. for 1 h, then at 110° C. overnight. LCMS analysis showed that the reaction was complete. Solvent was evaporated under reduced pressure, and the residue was dried in a vacuum oven to give N-methyl-3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carboxamide, which was used directly for the next step. LCMS (ESI) m/z 370 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:9][NH:10][C:11](=[O:22])[C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([OH:19])[C:13]=1[O:20][CH3:21])[CH3:3].C(O)(=O)C.[Br:27]Br>O1CCOCC1>[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:9][NH:10][C:11](=[O:22])[C:12]1[C:13]([O:20][CH3:21])=[C:14]([OH:19])[CH:15]=[C:16]([Br:27])[C:17]=1[OH:18])[CH3:3]
Reactant: BrBr
Reactant: CCN1CCC[C@H]1CNC(=O)c1c(O)ccc(O)c1OC
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCN1CCC[C@H]1CNC(=O)c1c(O)c(Br)cc(O)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (S)-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-3,6-dihydroxy-2-methoxybenzamide hydrochloride (90 mg, 0.27 mmol), 0.5 ml dioxane and 0.1 ml acetic acid was added a solution of 18 μl bromine (0.35 mmol) in 0.5 ml dioxane. After stirring at room temperature for 1 h the solvent was evaporated.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])C.[NH2:25][CH:26]([CH3:29])[CH2:27][OH:28]>>[OH:28][CH2:27][CH:26]([NH:25][C:4]([C:6]1[S:10][C:9]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])[CH3:29]
Reactant: CCOC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)s1
Reactant: CC(N)CO
Product: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NC(C)CO)s1
Yield: 43 %

Procedure:
As described for example 127, 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-thiazole-5-carboxylic acid ethyl ester (200 mg, 0.56 mmol) was converted, using rac-2-amino-1-propanol instead of isopropylamine, to the title compound (94 mg, 43%) which was obtained as a colourless gum after purification by chromatography (silica, 0 to 3% methanol in dichloromethane). MS: m/e=374.0 [M+H]+.
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH2:14])=[CH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][C:23]#[N:24]>CC(C)=O>[NH2:14][C:4]1[CH:3]=[C:2]2[C:7](=[CH:6][CH:5]=1)[CH:8]1[CH2:12][CH2:13][CH:1]2[CH2:11][N:10]([CH2:22][C:23]#[N:24])[CH2:9]1
Reactant: N#CCBr
Reactant: Nc1ccc2c(c1)C1CCC2CNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#CCN1CC2CCC(C1)c1cc(N)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
10-Aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamine (193 mg, 1.02 mmol) was dissolved in acetone (20 mL) and Cs2CO3 (994 mg, 3.06 mmol, 3.0 eq) and bromoacetonitrile (134 mg, 1.13 mmol, 91 μL, 1.1 eq) were added. The reaction was stirred at room temperature for 2 hours and was then concentrated under reduced pressure. The residue was taken up in CH2Cl2 (10 mL) and washed with water (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent to obtain (4-amino-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-acetonitrile as a brown oil (123 mg, 53%). LCMS (m/e) 227 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 6.87 (d, 1H, J=7.7 Hz), 6.50 (dd, 1H, J=2.4 and 7.7 Hz), 6.47 (d, 1H, J=2.3 Hz), 3.57 (bs, 2H), 3.52 (s, 2H), 3.00-2.90 (m, 2H), 2.99-2.80 (m, 2H), 2.61-2.50 (m, 2H), 2.20-2.05 (m, 2H), 1.70-1.63 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[SH:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[S:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:20][CH:21]=1)([O-:14])=[O:13]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(Sc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
The title compound was prepared from 1-Chloro-2-nitro-4-trifluoromethyl-benzene (250 mg, 1.10 mmol), N-(4-Mercapto-phenyl)-acetamide (185 mg, 1.10 mmol), and K2CO3 (268 mg, 1.94 mmol) heated in DMF at 100° C. for 16 hrs. Reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate (350 mg, 88%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:6]=[CH:5][CH:4]=1.[C:19]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([N:7]3[C:3]([C:2]([F:1])([F:18])[F:17])=[CH:4][CH:5]=[N:6]3)=[CH:16][CH:15]=2)=[CH:28][CH:29]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)c1ccc(-n2nccc2C(F)(F)F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-n3nccc3C(F)(F)F)cc2)cc1
Temperature: 65 °C

Procedure:
The product from Example 37A (37.3 mg, 0.146 mmol), 4-tert-butylaniline (28 μL, 0.18 mmol), PS-DCC (1.27 mmol/g, 0.342 g, 0.435 mmol), HOBT (20.2 mg, 0.149 mmol), and triethylamine (0.062 mL, 0.45 mmol) in DMF (1.5 mL) were combined and heated at 65° C. for 16 hours. The mixture was allowed to cool to room temperature, filtered, and the filtrate was diluted with diethyl ether (20 mL). The diethyl ether was washed with water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (15% ethyl acetate in hexanes) to provide the title compound as a solid. 1H NMR (300 MHz, CDCl3) δ 7.99 (d, 2H), 7.83 (br s, 1H), 7.76 (m, 1H), 7.63 (d, 2H), 7.52 (d, 2H), 7.41 (d, 2H), 6.87 (m, 1H), 1.33 (s, 9H); MS (m/z) 388.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4]([CH2:18][CH2:19][CH3:20])=[CH:5][C:6](=[O:17])[O:7]2.CO[CH:23](OC)[CH2:24][C:25]([CH3:28])(O)[CH3:26]>N1C=CC=CC=1>[CH3:26][C:25]1([CH3:28])[O:1][C:2]2[C:3]3[C:4]([CH2:18][CH2:19][CH3:20])=[CH:5][C:6](=[O:17])[O:7][C:8]=3[C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[C:10]([OH:12])[C:11]=2[CH:23]=[CH:24]1
Reactant: CCCc1cc(=O)oc2c(C(=O)CC)c(O)cc(O)c12
Reactant: COC(CC(C)(C)O)OC
Solvent: c1ccncc1
Product: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Yield: 79.1 %

Procedure:
A mixture of 3 (2.60 g, 9.42 mmol) and 4,4-dimethoxy-2-methylbutan-2-ol (5.54 g, 37.7 mmol) were dissolved in anhydrous pyridine (6.5 mL). The mixture was refluxed under nitrogen for three days. After removal of the solvent in vacuo, the residue was dissolved in ethyl acetate. The ethyl acetate was washed several times with 1N HCl and brine. It was then dried over Na2SO4. The crude product obtained by evaporation in vacuo was purified by silica gel column chromatography, eluting with 25% ethyl acetate/hexane to afford 2.55 g of 4 in 78.6% yield, mp 96°-98° C. 1H-NMR (CDCl3) δ 1.05 (3H, t, J=7.3 Hz, CH3); 1.22 (3H, t, J=7.5 Hz, CH3); 1.53 (6H, s, 2 CH3); 1.75 (2H, m, CH2); 2.92 (2H, t, J=7.1 Hz, CH2); 3.35 (2H, q, J=7.1 Hz, CH2); 5.56 (1H, d, J=10.0 Hz, H3); 5.98 (1H, s, H9); 6.72 (1H, d, J=10.0 Hz, H4); MS (EI): 343 (5.7, M+1); 342 (22.5, M+); 327 (100, M--CH3); IR (KBr): 1728 (vs, C=O) cm-1; Anal. calcd. for C20H22O5 : C, 70.16; H, 6.48; Found: C, 70.45; H, 6.92.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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.O>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccnc(Cl)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: O
Solvent: COCCOC
Product: Clc1ccnc(-c2ccccc2)c1
Yield: 88.3 %

Procedure:
A 1 L round bottom flask was charged with 2,4-dichloropyridine (30 g, 203 mmol), phenylboronic acid (24.7 g, 203 mmol), potassium carbonate (84 g, 608 mmol), Pd(PPh3)4 (2.3 g, 2.0 mmol), dimethoxyethane (500 mL) and water (150 mL). The mixture was degassed and heated to reflux for 20 h. After cooling, the aqueous layer was extracted with EtOAc; the organic portion was combined and subjected to column chromatography (SiO2, 5% EtOAc in hexane to 10% EtOAc in hexane) to give 34 g (88%) of 4-chloro-2-phenylpyridine. The product was confirmed by GC/MS and NMR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C@H:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][C@@H:28]2[F:40])=[C:24]([Cl:43])[CH:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1.Cl>CC(O)C.O1CCOCC1>[Cl:43][C:24]1[CH:23]=[C:22]([NH:21][C:2]2[N:7]=[C:6]([NH:8][C@@H:9]3[CH2:17][C@H:16]4[N:12]([CH2:13][CH2:14][CH2:15]4)[C:11]([CH3:19])([CH3:18])[CH2:10]3)[C:5]([F:20])=[CH:4][N:3]=2)[CH:42]=[CH:41][C:25]=1[O:26][C@H:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@@H:28]1[F:40]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(N)cc2Cl)[C@@H](F)C1
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CC1(C)C[C@H](Nc2nc(Nc3ccc(O[C@H]4CCNC[C@@H]4F)c(Cl)c3)ncc2F)C[C@@H]2CCCN21
Temperature: 100 °C
Yield: 50 %

Procedure:
A mixture of (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amine (0.2 g, 1.0 eq, 0.6 mmol), tert-butyl (3S,4S)-4-(4-amino-2-chlorophenoxy)-3-fluoropiperidine-1-carboxylate (0.2 g, 1.0 eq, 0.64 mmol) and PTSA (0.1 g, 0.9 eq, 0.6 mmol) was taken in iPrOH (10 mL) and heated at 100° C. for over night. After 18 hours of heating, reaction mixture was cooled to room temperature and PTSA (1.0 eq) was added to complete the deprotection of the Boc group. Then the reaction mixture was heated at 100° C. for 3 hours while stifling and cooled to room temperature. The volatiles were removed under vacuum to leave a crude solid. 4N HCl in dioxane (5 mL) was added to the crude mixture to ensure complete dprotection of the Boc group and the mixture was concentrated to dryness. Work-up and purification conditions used were the same as in Example 89 above for Compound 119, and gave the product as a solid in 50% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])C#N)[C:3]=1[CH3:21].P(=O)(O)(O)[OH:23]>O>[OH:23][C:2]1[C:3]([CH3:21])=[C:4]([CH2:9][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[N:5]=[C:6]([CH3:8])[N:7]=1
Reactant: O=P(O)(O)O
Reactant: Cc1cc(C)c(C(C#N)c2nc(C)nc(Cl)c2C)c(C)c1
Solvent: O
Product: Cc1cc(C)c(Cc2nc(C)nc(O)c2C)c(C)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of 6-chloro-2,5-dimethylpyrimidin-4-yl-(2,4,6-trimethylphenyl)-acetonitrile (1.5 g, 5.0 mmol) and 60 ml of 85% phosphoric acid was heated at reflux for 2 hours. The mixture was cooled at rt and diluted with water and extracted with chloroform. The organic layer was washed with brine, dried and concentrated to give 1.21 g (95%) of the title compound as a white solid, mp 260-262° C.
Reaction SMILES: [C:1]([C:6]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]3[O:18][CH2:17][O:16][C:11]=3[CH:12]=2)[CH:7]1[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1)([O:3][CH2:4][CH3:5])=[O:2].BrN1C(=[O:42])CCC1=O>>[C:31]([C:6]1([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:15][C:14](=[O:42])[C:13]2[C:8](=[CH:9][C:10]3[O:18][CH2:17][O:16][C:11]=3[CH:12]=2)[CH:7]1[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1)([O:33][CH2:34][CH3:35])=[O:32]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(C(=O)OCC)CCc2cc3c(cc2C1c1cc(OC)c(OC)c(OC)c1)OCO3
Product: CCOC(=O)C1(C(=O)OCC)CC(=O)c2cc3c(cc2C1c1cc(OC)c(OC)c(OC)c1)OCO3

Procedure:
In a small Pyrex tube equipped with a spin bar was added 50 mg of 2,2-dicarbethoxy-1-(3',4',5'-trimethoxyphenyl)-6,7-methylenedioxytetralin (XIV-b; R2 = ethyl) and 72 mg (4.0 eq) of N-bromosuccinimide (recrystallized from water). Dioxane (2 ml) was distilled in (from (Na/benzophenone), and the tube was sealed and placed under nitrogen. The mixture was irradiated for 2 min with a sunlamp while cooling with a cold water stream. Water (+μl) was then syringed in and irradiation and cooling was maintained for 18 to 20 min. The reaction mixture was then poured into saturated sodium bisulfite and extracted three times with chloroform. The organic layer was washed twice with 2N sodium hydroxide, twice with water, once with saturated brine, and was dried over sodium sulfate. Filtration and evaporation gave the title product (XV; R2 = ethyl) plus the ring bromination product at C-2' (<10%). One crystallization from methanol gave 46 mg (90%) pure title product, mp 152°-153°.