Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH:15]2C[CH2:16]2)[CH2:12][CH2:11][CH2:10][CH2:9]1.[H][H]>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: c1nc(-c2cnn(C(CC3CC3)C3CCCC3)c2)c2cc[nH]c2n1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 2 h
Yield: 68.9 %

Procedure:
4-[1-(1-Cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt (prepared in Example 729) (20 mg, 0.048 mmol) was dissolved in methanol (2 mL) and a catalytic amount of 5% Pd—C was added. The mixture was stirred under 1 atmosphere of hydrogen via an affixed balloon. After 2 hours, the mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) to afford the product (14 mg, 69%).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH2:16][CH:15]4[N:11]([CH2:12][CH2:13][CH2:14]4)[CH2:10][C:9]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]>CN(C=O)C>[N:23]1([C:21](=[O:22])[CH2:20][N:7]2[C:8]3[CH2:16][CH:15]4[N:11]([CH2:12][CH2:13][CH2:14]4)[CH2:10][C:9]=3[C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]2=3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: c1cnc2[nH]c3c(c2c1)CN1CCCC1C3
Reactant: O=C(CCl)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1c2c(c3cccnc31)CN1CCCC1C2)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine (70 mg, 0.32 mmol) in DMF (1 mL) was added a suspension of NaH (40.0 mg, 0.986 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of 2-chloro-1-(piperidin-1-yl)ethanone (159 mg, 0.986 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 3 h. The progress of reaction was monitored by TLC and NMR. The reaction mixture was diluted with ice-water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel flash chromatography (10% MeOH-DCM) to yield 1-(piperidin-1-yl)-2-(8,9,9a,10-tetrahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizin-11(7H)-yl)ethanone;
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:32])[NH:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([O:20]C(=O)C4C=CC([N+]([O-])=O)=CC=4)[CH2:16][CH2:15]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Na+]>C1COCC1>[OH:20][C@@H:17]1[CH2:18][CH2:19][C@H:14]([NH:13][C:12]([NH:11][C:1]23[CH2:2][CH:3]4[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]4)[CH2:10]2)[CH2:8]3)=[O:32])[CH2:15][CH2:16]1
Reactant: O=C(NC12CC3CC(CC(C3)C1)C2)N[C@H]1CC[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NC12CC3CC(CC(C3)C1)C2)N[C@H]1CC[C@@H](O)CC1
Reaction time: 8 h

Procedure:
To a solution of ester 1076 (1 g, 2.3 mmol) in THF (100 mL) was added 1N NaOH solution (4.6 mL, 4.6 mmol) at room temperature. The reaction mixture was stirred overnight, at which time the reaction was quenched by addition of 1N HCl solution (5.5 mL). The resulting white precipitate was collected by filtration and recrystallized from methanol/water. Yield: 0.63 g (95% of theory). M.P.: 205° C. 1H NMR (300 MHz, DMSO-d6): δ 5.67 (d, J=8.2 Hz, 1H), 5.45 (s, 1H), 4.41 (s, 1H), 3.63-3.51 (m, 1H), 3.46-3.36 (m, 1H), 2.00-1.92 (m, 3H), 1.87-1.72 (m, 6H), 1.66-1.28 (m, 14H).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1.NN.CCCCCC>C(O)COCCO>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2-c2ncccc21
Agent: NN
Solvent: OCCOCCO
Solvent: CCCCCC
Product: c1ccc2c(c1)Cc1cccnc1-2

Procedure:
Following the procedure described in Example 608, Part C, 3.45 g (19 mmole), of 4-azafluoren-9-one, 6.8 g (0.213 mole) of hydrazine in 50 ml of diethyleneglycol were combined and heated to 205° over a 30-minute period. TLC showed no remaining starting material. Identical workup yielded 2.33 g of pure 4-azafluorene, Rf-0.46 (hexane ethylacetatetriethylamine, 29.75:69.46:0.79).
Reaction SMILES: C([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=O)C.Cl.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].C(N(CC)CC)C>C1C=CC=CC=1>[OH:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:8]
Reactant: COC(=O)CCCCCN
Reactant: COc1cccc(C(=O)Cl)c1OC(C)=O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCNC(=O)c1cccc(OC)c1O
Yield: 54.9 %

Procedure:
2.3 g (10 mmol) of 2-acetoxy-3-methoxybenzoyl chloride dissolved in 18 ml of anhydrous benzene were dropwise added to the suspension of 1.80 g (10 mmol) methyl 6-aminohexanoate hydrochloride in 2.2 g (22 mmol) of anhydrous triethylamine and 18 ml of anhydrous benzene under nitrogen at room temperature while stirring. After boiling under reflux for 2 hours while stirring, the reaction mixture was cooled down, the precipitate was filtered by suction and the filtrate was evaporated. 20 ml of water were portionwise added to the residue, the solution was extracted with ethyl acetate, the organic phase was washed with 1 M hydrochloric acid and water, then dried. The solvent was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column by using a 3:4 mixture of petroleum ether and ethyl acetate to obtain 1.62 g (55%) of the title compound, m.p.: 69°-70° C.
Reaction SMILES: [C:1]1([CH2:11][C@H:12]2[C:16](=[O:17])[O:15][CH2:14][N:13]2[C:18]([O:20][CH2:21][CH:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH:24]1[C:23]2[CH:22]([CH2:21][O:20][C:18]([N:13]([CH3:14])[C@@H:12]([CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[C:16]([OH:17])=[O:15])=[O:19])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: O=C1OCN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]1Cc1cccc2ccccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](Cc1cccc2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (S)-(9H-fluoren-9-yl)methyl 4-(naphthalen-1-ylmethyl)-5-oxooxazolidine-3-carboxylate (0.750 g, 1.669 mmol) in DCM (8.0 ml) was added trifluoroacetic acid (8.0 mL, 104 mmol) followed by triethylsilane (0.799 ml, 5.01 mmol). The reaction mixture was allowed to stir at room temperature for 24 hours. Reaction mixture was dried on rotovap. The crude oil was dissolved in 15.0 mL of DCM and evaporated on rotovap twice. The crude product was obtained as an off-white gum and was purified by silica gel chromatography using dichloromethane and methanol as eluant. The desired product, (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(naphthalen-1-yl)propanoic acid, was obtained as a colorless gum (0.692 g, 46%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:40])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([C:29](=[O:39])[C:30]#[C:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:16]=1>>[CH3:12][O:13][C:14](=[O:40])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:30](=[C:31](/[C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)\[C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)/[C:29]2=[O:39])[CH:16]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccc(Cl)cc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccc(Cl)cc3)c3ccc(C(F)(F)F)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-iodo-4-trifluoromethyl-benzene (commercially available) and 3-({[3-(4-chloro-phenyl)-propynoyl]-phenyl-amino}-methyl)-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.91 (s, 3H), 4.96 (s, 2H), 6.37 (d, 1H), 6.66-6.71 (m, 2H), 7.08 (t, 1H), 7.26-7.52 (m, 9H), 7.73 (d, 2H), 7.94 (d, 1H), 8.01 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)/[CH:25]=[C:26](/[O:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[F:37])\[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=2[F:37])=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)/C=C(\CBr)Oc1cc(C)ccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cc(C)ccc2F)=CC1=O
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 43.2 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.82 g, 4.56 mmol) in acetonitrile (11.4 mL) was treated with N,N-diisopropylethylamine (0.74 mL, 4.48 mmol). After addition was complete, the mixture was stirred at 60° C. for 45 min. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.74 mL, 4.48 mmol) and acetonitrile (11.4 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of (E)-4-bromo-3-(2-fluoro-5-methyl-phenoxy)-but-2-enoic acid ethyl ester (1.31 g, 4.14 mmol) in acetonitrile (10.4 mL). After the addition was complete, the reaction mixture was heated to 100° C. where it stirred for 24 h. At this time, the reaction mixture was cooled to 25° C. and was stirred at 25° C. for 2 d. The reaction was then concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 10-50% ethyl acetate/hexanes) afforded (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.60 g, 43%) as an orange oil: HR-ES-MS m/z calculated for C18H22NO4F [M+H]+ 336.1606, observed 336.1607; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H), 1.34-1.53 (m, 1H), 1.53-1.69 (m, 1H), 1.72-1.89 (m, 1H), 2.31 (s, 3H), 3.66 (s, 3H), 4.18 (d, J=18.4 Hz, 1H), 4.25 (d, J=18.4 Hz, 1H), 4.73 (dd, J=11.3, 4.4 Hz, 1H), 4.90 (s, 1H), 7.11-7.20 (m, 1H), 7.26-7.38 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[C:11]=1[CH3:17])([CH3:6])([CH3:5])[CH3:4].Cl[C:21]1[S:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=1.Cl>O.C1COCC1>[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:21]2[S:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=2)[C:11]=1[CH3:17])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1c(C(C)(C)O[SiH2]C(C)(C)C)ccnc1N
Reactant: N#Cc1cnc(Cl)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(C)(C)O[SiH2]C(C)(C)C)ccnc1Nc1ncc(C#N)s1
Temperature: 25 °C

Procedure:
An oven dried flask under N2 was charged with NaH (60% dispersion, 210 mg, 5.25 mmol). 5 mL of anhydrous THF was added followed by 4-(tert-butyl-dimethyl-silanyloxymethyl)-3-methyl-pyridin-2-ylamine (10-2, 0.602 g, 2.39 mmol) and 2-chloro-5-cyanothiazole (1-2, 0.414 g, 2.86 mmol). The resulting solution was heated to reflux. After 19 hours additional NaH (19 mg, 0.48 mmol) and 2-chloro-5-cyanothiazole (1-2, 0.069 g, 0.48 mmol) were added. After an additional 1 hour at reflux the reaction was allowed to cool to room temperature and diluted with water. The pH was adjusted to 7 with 1 M HCl. The resulting precipitate was filtered and washed with water to afford 10-3. 1H NMR (CDCl3) δ 8.41 (bs, 1H), 8.27 (d, 1H, J=5.2 Hz), 7.94 (s, 1H), 7.19 (d, 1H, J=5.2 Hz), 4.74 (s, 2H), 2.21 (s, 3H), 0.96 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[N:11]=1)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>>[CH3:1][NH:2][C:10]1[N:11]=[C:12]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Product: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A mixture of tert-butyl methyl[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]carbamate (0.60 g, 1.6 mmol) and trifluoroacetic acid (8 ml) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure to give crystals, which were recrystallized from methanol-diethyl ether to give the titled compound (0.33 g, 74%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([P:17]([C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH3:36])=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2Br)[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].Cl[P:42]([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45]>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([P:17]([C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH3:36])=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[P:42]([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOP(Cl)OCC
Reactant: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2Br)cc1C(C)(C)C
Solvent: C1CCOC1
Product: CCOP(OCC)c1ccccc1P(c1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1)c1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
Into a four-neck flask was weighed 15.00 g (24.0 mmol) of the bis(3,5-di-t-butyl-4-methoxyphenyl)(2-bromophenyl)phosphine (7). The atmosphere of the reaction vessel which was fitted with a thermometer, a condenser tube, and a dropping funnel with a pressure-equalizing tube was completely replaced with nitrogen, and 150 mL of anhydrous tetrahydrofuran (hereinafter referred to as THF) was added thereto. Thereto was added dropwise 16.2 mL (25.2 mmol) of n-butyllithium-hexane (1.6 M) solution at −78° C. over a period of 30 minutes, followed by 1 hour of stirring at the same temperature. The resulting mixed solution was cooled to −78° C. and thereto was added dropwise a 10 mL THF solution of 4.15 g (25.2 mmol) of diethyl chlorophosphonite (manufactured by Aldrich) over a period of 30 minutes. After the dropwise addition, a cooling bath was removed and the whole was further stirred at room temperature for 15 hours. After the completion of the reaction, THF was removed by evaporation, the residue was dissolved in 50 mL of diethyl ether, and insoluble matter was removed by filtration. The solvent was removed by evaporation and the residue was purified by active alumina column chromatography (eluent: hexane/ethyl acetate 4/1) to obtain the title compound (14.03 g, a pale yellow solid) Yield 91.5%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH2:20]([NH2:23])[CH2:21][CH3:22]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:12]#[N:13])=[C:6]([NH:23][CH2:20][CH2:21][CH3:22])[N:7]=1
Reactant: CCCN
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Solvent: COCCOC
Product: CCCNc1nc(N)nc(-c2ccccc2)c1C#N

Procedure:
From 2-amino-4-methanesulfonyl-6-phenyl-pyrimidine-5-carbonitrile and propylamine in DME. ES-MS m/e (%): 254 (M+H+, 100).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][C:12]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)=O>>[C:2]1([C:1]2[S:8][CH:11]=[C:12]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=S)c1ccccc1
Product: CCOC(=O)c1ccc(-c2csc(-c3ccccc3)n2)cc1
Yield: 68 %

Procedure:
In the same manner as in Example 74, thiobenzamide was reacted with ethyl 4-bromoacetylbenzoate to obtain ethyl 4-(2-phenyl-4-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 68%. Pale yellow prisms. Melting point: 72 to 73° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:5][C:6]=1[Cl:7].C([O-])(=O)C.[Na+].[H][H]>[Pd].C(O)C>[Cl:7][C:6]1[CH:5]=[C:4]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[S:3][CH:2]=1
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)c(Br)s1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(c1ccc(F)cc1)c1cc(Cl)cs1
Reaction time: 3 h

Procedure:
A slurry of 5% palladium on charcoal (20 g) in ethanol (100 ml) was added under nitrogen gas to a solution of the above 2-bromo3-chloro-5-(4-fluorobenzoyl)-thiophene (299.4 9 ) in ethanol (3.400 ml), containing sodium acetate (77.0 g),and the mixture was hydrogenated for 3 hours at room temperature and pressure (total uptake of hydrogen was 22,994 ml). The reaction mixture was filtered through a dicalite pad and the pad was washed with ethanol (2×200 ml). The filtrate was taken to low volume (approximately 2 l) and added to water (17 l). The precipitate was filtered and while damp it was dissolved in dichloromethane (1 l) which was then reduced in volume to approximately 500 ml. Methanol (500 ml) was added and the remainder of the dichloromethane was removed by distillation. The resultant crystals were filtered and dried to give 4-chloro-2-(4-fluorobenzoyl)thiophene as a white solid (169 g). A second crop (19.2 g) was obtained and recrystallised from dichloromethane/methanol to give more of the purified product (12.9 g). The crops were combined and used in the next stage.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][CH:9]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:27]>CN(C=O)C.O>[CH3:27][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=1)([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)OC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C(C)(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
A 250-mL round bottom flask was charged with diisopropyl 2-(4-nitrobenzyl)malonate (1.61 g, 4.98 mmol) in DMF (24 mL). To this solution at 0° C. was slowly added NaH (60% suspension, 0.24 g, 5.97 mmol). After 30 minutes, iodomethane (0.37 mL, 5.97 mmol) was added in one portion. The reaction was stirred for 21 h, at which time, the reaction was warmed to rt. The reaction was diluted in water (250 mL) and extracted with methyl tert-butylether (3×75 mL). The combined extract was washed with saturated sodium chloride (2×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 8:2) as eluent to afford the title compound (1.44 g, 86%) as a white solid. MW=337.37. 1H NMR (CDCl3, 300 MHz) δ 8.16-8.09 (m, 2H), 7.37-7.30 (m, 2H), 5.05 (sept, J=6.3 Hz, 2H), 3.30 (s, 2H), 1.33 (s, 3H), 1.27-1.20 (m, 12H).
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16]([O:18]C)=O)=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[S:25][C:26]([CH3:29])=[CH:27][N:28]=1>>[CH3:1][N:2]1[C:15]([C:16]([NH:23][C:24]2[S:25][C:26]([CH3:29])=[CH:27][N:28]=2)=[O:18])=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21]
Reactant: COC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1C
Reactant: Cc1cnc(N)s1
Product: Cc1cnc(NC(=O)C2=C(O)c3c(c4ccccc4n3C)S(=O)(=O)N2C)s1
Yield: 90 %

Procedure:
2,5-Dihydro-2,5-dimethyl-4-hydroxy-N-(5-methyl-2-thiazolyl)-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from methyl 2,5-Dihydro-2, 5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate 1,1-dioxide and 2-amino-5-methyl-thiazole with a yield of 90% of theory; M.p.: 250° C. (decomposition).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][NH:11][C:10]=1[CH3:22])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]([OH:21])[C:17]([F:20])([F:18])[F:19])=[CH:12][NH:11][C:10]=1[CH3:22]
Reactant: [H][H]
Reactant: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1O
Yield: 84 %

Procedure:
3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (0.5 g, 1.60 mmol) was dissolved in methanol and hydrogenated over 10% Pd/C for 3 hrs at 50 psi hydrogen on a Parr hydrogenator. The mixture was filtered through CELITE™ and the filtrate was evaporated to give a solid (300 mg, 84.2%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH:42]2[CH2:47][CH2:46][CH:45]([N:48]([CH3:50])[CH3:49])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([CH:42]4[CH2:43][CH2:44][CH:45]([N:48]([CH3:49])[CH3:50])[CH2:46][CH2:47]4)=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1Cc2c(C3CCC(N(C)C)CC3)ccc(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4CCC(N(C)C)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-4-[4-(dimethylamino)cyclohexyl]-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 233A). 1H NMR (CD3OD, 400 MHz): δ=1.30 (t, J=7.07 Hz, 6H), 1.75-1.85 (m, 2H), 1.85-2.02 (m, 4H), 2.39 (d, J=14.15 Hz, 2H), 2.77-2.88 (m, 1H), 3.04 (s, 6H), 3.18 (s, 3H), 3.38-3.50 (m, 3H), 3.86 (s, 3H), 4.07-4.20 (m, 4H), 4.51 (s, 2H), 7.01-7.07 (m, 1H), 7.12 (t, J=2.15 Hz, 1H), 7.62 (d, J=8.59 Hz, 2H), 8.32-8.42 (m, 2H). MS (ES+): m/z 705.26 [MH+] (TOF, polar).
Reaction SMILES: Cl.[C:2]([O:6][C:7]([C:9]1[S:10][C:11]([CH2:14][CH2:15][CH2:16][NH2:17])=[CH:12][CH:13]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[Br:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][CH:27]=O)[CH:22]=[CH:23][CH:24]=1>>[C:2]([O:6][C:7]([C:9]1[S:10][C:11]([CH2:14][CH2:15][CH2:16][NH:17][CH2:27][CH2:26][CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Br:18])[CH:20]=2)=[CH:12][CH:13]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=CCCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCN)s1
Agent: Cl
Product: CC(C)(C)OC(=O)c1ccc(CCCNCCCc2cccc(Br)c2)s1

Procedure:
The title compound was prepared from 5-(3-amino-propyl)-thiophene-2-carboxylic acid tert-butyl ester hydrochloride and 3-(3-bromo-phenyl)-propionaldehyde following the method described in Step A of Example 141. 1H NMR (400 MHz, CDCl3) δ 7.50 (d, 1H), 7.28-7.30 (m, 2H), 7.06-7.14 (m, 2H), 6.75 (d, 1H), 2.85 (t, 2H), 2.65-2.78 (m, 4H), 2.60 (t, 2H), 1.92-2.04 (m, 4H), 1.52-1.54 (m, 9H); MS 438 (M+).