Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH:10]([CH3:12])[CH3:11]>CN(C)C=O>[Br:1][C:2]1[N:3]=[CH:4][N:5]([CH:10]([CH3:12])[CH3:11])[CH:6]=1
Reactant: Brc1c[nH]cn1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cnc(Br)c1
Temperature: 0 °C
Yield: 29.6 %

Procedure:
A mixture of 4-bromo-1H-imidazole (1.0 g, 6.80 mmol) in dimethylformamide (5 mL) was stirred at 0° C., to which was added sodium hydride, 60% suspension in oil, (326 mg, 8.20 mmol). The reaction mixture was warmed to room temperature and stirred for 30 minutes, followed by dropwise addition of 2-bromopropane (0.70 mL, 7.48 mmol). The reaction mixture was stirred at room temperature for 15 hours under nitrogen, then quenched with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with water (20 mL) and extracted with 1M hydrochloric acid (3×20 mL). The combined acidic extracts were washed with ethyl acetate (20 mL), then basified with ammonium hydroxide (pH 12), and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Preparative HPLC, eluting with an ethyl acetate-isohexane gradient, gave the product as a pale brown oil (380 mg, 30%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]([C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[N:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.NO.[CH2:33]([N:35](CC)CC)[CH3:34].C(OC(=O)C)(=[O:42])C>CCO>[C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]([C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[N:35]=[C:33]([CH3:34])[O:42][N:28]=3)=[CH:25][CH:26]=2)[N:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc(-c2ccc(C#N)cc2)c[nH]1
Agent: Cl
Agent: NO
Solvent: CCO
Product: Cc1nc(-c2ccc(-c3c[nH]c([C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)n3)cc2)no1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
{(S)-1-[4-(4-Cyanophenyl)-1H-imidazol-2-yl]-2-phenylethyl}carbamic acid tert-butyl ester prepared as described in Example 28 Part A (1.00 equiv; 2.57 mmoles; 1.00 g) was dissolved in 15 mL EtOH and Hydroxylamine Hydrochloride (12.87 mmoles; 894.42 mg) and Triethylamine (12.87 mmoles; 1.79 mL) were added. The resulting solution was heated at reflux in an 80° C. oil bath under N2 overnight. Reaction was cooled to room temperature and evaporated to remove EtOH. Residue was suspended in a mixture of EtOAc/EtOH (˜10:1) and filtered to remove inorganic solids. Filtrate was reconcentrated to a yellow foam. This residue was redissolved in 10 mL HOAc and treated with stirring under N2 with Acetic Anhydride (4.23 mmoles; 400 μL). Solution was stirred for 20 min at room temperature, then heated in 80° C. oil bath for 2 h, cooled to room temperature and stirred overnight. Most of HOAc was removed on rotary evaporator, then residue was diluted with water and carefully neutralized by addition of sat'd NaHCO3 to pH˜8. Extracted 3× with CH2Cl2. Combined extracts were washed with brine then dried over MgSO4, filtered and evaporated to a lt red foam. Residue was purified on silica gel to provide the product as a lt pinkish tan foam. (590 mg; 51.4%). 1H NMR (500 MHz, CDCl3) δ 1.41 (s, 9H) 2.65 (s, 3H) 3.28-3.44 (m, 2H) 4.88 (d, J=7.70 Hz, 1H) 5.23 (s, 1H) 7.13-7.36 (m, 5H) 7.42-7.55 (m, 1H) 7.88 (d, J=8.25 Hz, 2H) 8.06 (d, J=8.25 Hz, 2H) 9.67 (s, 1H). m/z 446.1 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([O:28]C)=[O:27])[CH2:10]2)=[O:8])[CH2:3]1.CC(C)([O-])C.[K+]>>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:26]([OH:28])=[O:27])[CH2:10]2)=[O:8])[CH2:3]1
Reactant: COC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)C2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)C2)C1

Procedure:
26.05 g (16.06 mmol) of the compound from Example 111A were reacted with 26.05 g (160.6 mmol) of potassium tert-butoxide according to the General Method 9A. Yield: 5.9 g (91% of theory).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH2:17]([CH:19]([CH2:23][CH2:24][CH2:25][CH3:26])[C:20](O)=[O:21])[CH3:18]>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:20](=[O:21])[CH:19]([CH2:17][CH3:18])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Reactant: CCCCC(CC)C(=O)O
Product: CCCCC(CC)C(=O)NC(CC)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 58A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 97 mg (0.67 mmol) 2-ethyl-hexanoic acid and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][C:5]([F:21])=[CH:4][N:3]=1.O1CCCC1.[OH-].[Na+].Cl[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=1>CN(C)C=O>[F:21][C:5]1[CH:6]=[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=4)=[CH:16][CH:15]=3)[CH:9]=2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(F)cc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: Fc1ccc(CCl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ncc(F)cc1-c1cc(Cc2ccc(OCc3ccc(F)cn3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To 4-(5-(2-amino-5-fluoro-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (20.0 mg, 0.07 mmol) described in Manufacturing Example 174-1-1 were added tetrahydrofuran (3 mL) and a 5 N sodium hydroxide aqueous solution (14.0 μL, 0.07 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. Next, the reaction solution was concentrated under a reduced pressure, which gave a white solid. To a mixture of this solid and N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-5-fluoro-pyridine (11.2 mg, 0.08 mmol) described in manufacturing Example 41-1-2, which was stirred for 1 hour at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (24.7 mg, 89%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[S:29][CH:30]=[C:31]([CH2:33][NH:34][CH2:35][CH2:36][CH2:37]OC)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:43][O:44][CH2:45]CCN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[S:29][CH:30]=[C:31]([CH2:33][N:34]5[CH2:2][CH2:37][CH2:36][C@H:35]5[CH2:43][O:44][CH3:45])[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:12])=[O:11])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNCCCOC)cs4)cc23)CC1
Reactant: COCCCN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CN5CCC[C@H]5COC)cs4)cc23)CC1
Yield: 4.6 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[3-(methyloxy)propyl]amino}methyl)-2-thienyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (2S)-2-[(methyloxy)methyl]pyrrolidine (115.18 mg, 1 mmol) for 3-(methyloxy)-1-propanamine to afford 3 mg of the title compound (4.6%).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH:6]1([S:9](Cl)(=[O:11])=[O:10])[CH2:8][CH2:7]1>C1COCC1>[C:1]([NH:5][S:9]([CH:6]1[CH2:8][CH2:7]1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)C1CC1
Temperature: -20 °C
Reaction time: 18 h
Yield: 83.2 %

Procedure:
To a round-bottom flask equipped with a stir bar was added tert-butylamine (32.9 mL, 313 mmol) and dry THF (330 mL). The solution was cooled to −20° C. and to the stirred solution was added dropwise cyclopropanesulfonyl chloride (14.5 mL, 142 mmol). The solution was allowed to warm to room temperature with stirring for 18 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DCM, washed with 1N HCl; water; and then brine. The organic solution was dried over MgSO4, filtered, and then concentrated in vacuo. The resulting solid was recrystallized from hexanes:EtOAc (5:1) to afford N-(tert-butyl)cyclopropanesulfonamide as a colorless crystalline solid (20.95 g, 83%). 1H NMR (400 MHz, CDCl3) δ 4.22 (br. s., 1H), 2.47 (tt, J=8.0, 4.9 Hz, 1H), 1.40 (s, 9H), 1.22-1.16 (m, 2H), 1.04-0.97 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[N:29]=[C:28]([NH:30][C@H:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:32][OH:33])[CH2:27][S:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:27]2/[C:28]([NH:30][C@H:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:32][OH:33])=[N:29][C:25](=[O:24])[S:26]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CN(C)C(=O)[C@H](CO)NC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C(=O)[C@H](CO)NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.47 g) in 2-propanol (10 mL) were added N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-N,N-dimethyl-L-serinamide (1.50 g) and piperidinium acetate (641 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) and silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (1.24 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.Br[CH:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]1=[O:37]>C(#N)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH:26]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]3=[O:37])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:9]=1
Reactant: CCOC(=O)CN1CCC(Br)C1=O
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN1CCC(N2CCC(C(=O)c3ccc(OC)cc3)CC2)C1=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
(4-Methoxyphenyl)(piperidin-4-yl)methanone hydrochloride (524 mg, 2.05 mmol) was stirred at room temperature with triethylamine (0.657 mL, 477 mg, 4.71 mmol) in acetonitrile (80 mL). A solution of ethyl 2-(3-bromo-2-oxopyrrolidin-1-yl)acetate (513 mg, 2.05 mmol) in acetonitrile (20 mL) was added to the mix. The reaction was stirred 3 hours at 40° C. and then overnight at 50° C. After 24 hours the reaction was not complete and the reaction was stirred an additional 48 hours at 70° C. then allowed to cool to room temperature. The solvents were removed in vacuo. The crude orange solid was eluted through a silica gel column with a 0 to 10% methanol/dichloromethane gradient to afford the title racemic compound (730 mg, 87% yield, 95% purity) as a thick amber oil. MS (ESI) [m/e, (M+H)+]=389.5. 1H NMR (400 MHz, chloroform-d) δ ppm 7.90-7.95 (m, 2H), 6.91-6.96 (m, 2H), 4.17-4.24 (m, 2H), 3.95-4.17 (m, 2H), 3.88 (s, 3H), 3.56-3.64 (m, 1H), 3.36-3.50 (m, 2H), 3.18-3.29 (m, 1H), 3.04-3.13 (m, 1H), 2.93-3.04 (m, 2H), 2.41-2.56 (m, 1H), 2.20-2.35 (m, 1H), 2.04-2.19 (m, 1H), 1.80-1.95 (m, 4H), 1.26-1.32 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].[CH:21]([S:23]([C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([S:32](Cl)(=[O:34])=[O:33])[CH:31]=1)(=[O:25])=[O:24])=[CH2:22]>C(Cl)Cl.N1C=CC=CC=1>[CH:21]([S:23]([C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([S:32]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)(=[O:11])=[O:10])(=[O:33])=[O:34])[CH:31]=1)(=[O:24])=[O:25])=[CH2:22]
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Reactant: C=CS(=O)(=O)c1ccc(OC)c(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CS(=O)(=O)c1ccc(OC)c(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2cc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-aminophenyl)-amide (10 mmol, prepared as in Example 1) in DCM (20 mL) and pyridine (20 mL), 5-ethenesulfonyl-2-methoxybenzenesulfonyl chloride (11 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (100 mL). The organic phase was washed with 10% aqueous HCl (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain benzo[b]thiophene-2-sulfonic acid [2-(5-ethenesulfonyl-2-methoxybenzenesulfonylamino)phenyl] amide (2.8 g). LC: Tr 1.15 min; MS: 565.9 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 4.17 (s, 3H), 6.03 (d, 1H), 6.42 (d, 1H), 6.56 (dd, 1H), 6.81 (dd, 1H), 6.97 (t, 1H), 7.13 (t, 1H), 7.18 (d, 1H), 7.32 (d, 1H), 7.42-7.52 (m, 2H), 7.62 (s, 1H), 7.80 (d, 1H), 7.83 (d, 1H), 8.04 (dd, 1H), 8.19 (d, 1H) ppm.
Reaction SMILES: [F:1][C@@:2]([CH3:25])([C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)=[O:7])[C:3](O)=[O:4].[F:26][C:27]([F:34])([C:30]([F:33])([F:32])[F:31])[CH2:28][NH2:29]>>[F:1][C@:2]([CH3:25])([C:3]([NH:29][CH2:28][C:27]([F:34])([F:26])[C:30]([F:33])([F:32])[F:31])=[O:4])[C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)=[O:7]
Reactant: C[C@@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Product: C[C@@](F)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21

Procedure:
In an analogous manner to that described in Example 1 c), the condensation of (2S)-2-fluoro-2-methyl-N-[(S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-malonamic acid and 2,2,3,3,3-pentafluoro-propylamine yielded the title compound as a white solid; MS: m/e=474 (M+H)+; optical integrity 96.4% d.e.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:7](=[O:16])[N:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[CH:4]=1)[NH2:2].[CH3:21][N:22]=[C:23]=S.CO>CN(C=O)C>[CH3:21][NH:22][C:23]1[C:4]2[C:5](=[O:20])[N:6]([CH2:17][CH2:18][CH3:19])[C:7](=[O:16])[N:8]([CH2:9][C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)[C:3]=2[NH:1][N:2]=1
Reactant: CN=C=S
Reactant: CCCn1c(=O)cc(NN)n(Cc2ccncc2)c1=O
Solvent: CO
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccncc2)c1=O
Reaction time: 14 h

Procedure:
A solution of 6-hydrazino-1-(4-pyridylmethyl)-3-propyluracil (1.5 g, 5.7 mM) and methyl isothiocyanate (1.55 ml, 23 mM) in DMF (15 ml) was heated at 90° C. for 14 hours and then at 110° C. for 14 hours. To the reaction solution was added 50% methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/ethanol/water afforded colorless needles (1.02 g, 57%), m.p. >300° C.
Reaction SMILES: [CH3:1][S:2]([O:5][CH3:6])(=[O:4])=[O:3].[Li]CCCC.[CH3:12][C:13]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:18]=[C:17]([B:28]2[O:32]C(C)(C)[C:30](C)(C)[O:29]2)[C:14]=1C=O>C1COCC1>[OH:32][B:28]1[C:17]2[CH:18]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:20]=[C:13]([CH3:12])[C:14]=2[CH:30]([CH2:1][S:2]([O:5][CH3:6])(=[O:4])=[O:3])[O:29]1
Reactant: Cc1cc(OC2CCCCO2)cc(B2OC(C)(C)C(C)(C)O2)c1C=O
Reactant: COS(C)(=O)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COS(=O)(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(C)c21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a cooled (−78° C.) solution of methyl methanesulfonate (1.56 mL, 20 mmol) in 15 ml anhydrous THF was added 1.6 M n-BuLi in hexanes (11.25 ml, 18 mmol) dropwise. The mixture was stirred at −78° C. for 20 minutes, then a solution of 2-methyl-4-(tetrahydro-2H-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.07 g, 6 mmol) in 15 mL THF was added slowly via syringe. After stirring at −78° C. for 10 minutes, the reaction was quenched with saturated ammonium chloride at −78° C. It was then extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give crude product, which was purified by flash column. (1.64 g) MS (ESI) m/z=713 [2M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][Si]([N-][Si](C)(C)C)(C)C.[K+].S(OC)(OC)(=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH3:22])[CH:9]1[CH:13]([O:14][CH3:23])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)OC(C)(C)C)CC1O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COC1CN(C(=O)OC(C)(C)C)CC1N(C)C(=O)OC(C)(C)C

Procedure:
Compound 6 (9.9 kg) was treated with a solution of KHMDS (35 kg, 20% w/w) in THF, followed by dimethyl sulfate (4.7 kg). After completion of the reaction, the reaction mixture was quenched with 5% acetic acid in water. The product was extracted with MTBE, and the organic layer concentrated to give crude product (7). This was treated with p-toluene sulfonic acid monohydrate (TsOH) in a tetrahydrofuran-methanol mixture. After completion of the reaction, the slurry was cooled and the product is isolated by filtration to give 12.2 kg of Compound 8.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH:23]4[CH2:25][CH2:24]4)[CH:22]=2)[O:19][C:18]([CH3:27])([CH3:26])[CH2:17][C:16]3([CH3:29])[CH3:28])=[CH:7][CH:6]=1.CO.[OH-].[Na+].O>C(#N)C>[CH:23]1([C:21]2[CH:22]=[C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:30])=[O:2])=[CH:10][CH:9]=3)[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([CH3:26])([CH3:27])[CH2:17][C:16]3([CH3:29])[CH3:28])[CH2:25][CH2:24]1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(CC(=O)O)cc3)cc(C3CC3)c2O1

Procedure:
Following general procedure L and using [4-(8-cyclopropyl-2,2,4,4-tetramethyl-chroman-6-ylethynyl)phenyl]acetic acid methyl ester (Compound 35, 0.137 g, 0.30 mmol), 5 mL of methanol and 1M sodium hydroxide solution (2 mL) followed by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a solid (0.11 g, 80%).
Reaction SMILES: [C:1]1([CH:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH2:25]=[O:26]>C1COCC1>[OH:26][CH2:25][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: C=O
Reactant: c1ccc(C2c3ccccc3-c3ccccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCC1(c2ccccc2)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 9-phenylfluorene (13.6 mmol) in THF (40 mL) is added nBuLi (1.2 eq) dropwise at 0° C. under an argon atmosphere. The resulting mixture is stirred at 0° C. for 30 min. Paraformaldehyde (1.2 eq) is added in one portion, and the resulting mixture is allowed to stir at room temperature overnight. The reaction mixture is quenched with saturated NH4Cl solution. The resulting mixture is extracted with EtOAc. The EtOAc layer is dried (Na2SO4) and concentrated in vacuo. The concentrate is purified by flash chromatography on silica gel eluting with hexanes-ethyl acetate to isolate the alcohol.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:4]=[CH2:5].[CH2:19]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])[CH3:20]>CN(C=O)C>[CH2:3]([C:6]([C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[CH2:19][CH3:20])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[CH:4]=[CH2:5]
Reactant: CCc1ccccc1C(=O)Cl
Reactant: C=CCC(C(=O)OCC)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC(C(=O)OCC)(C(=O)OC(C)(C)C)C(=O)c1ccccc1CC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67.6 %

Procedure:
Sodium hydride (2.8 g., 50% w/w dispersion in mineral oil) was added over 15 minutes to an ice cooled solution of t-butyl ethyl 2-allylmalonate (13.4 g.) in dry DMF (120 ml.) under nitrogen. The mixture was stirred at room temperature for 45 minutes and cooled to 0° C. 2-Ethylbenzoyl chloride (10.1 g.) was added over 2 minutes and the mixture stirred at room temperature for 18 hours. The DMF was evaporated and the residue shaken with water (100 ml.) and ethyl acetate (200 ml.). The ethyl acetate phase was separated, washed with saturated brine, dried (MgSO4) and evaporated. The oil obtained (21.8 g.) was purified by flash column chromatography on silica (650 g.) using toluene as eluant to give t-butyl ethyl 2-allyl-2-(2-ethylbenzoyl)malonate (14.3 g.) as an oil; NMR: 1.25 (15H,m), 2.7 (2H,q), 2.9 (2H,d), 4.12 (2H,q), 5.31 (2H,m), 6.05 (1H,m) and 7.35 (4H,m) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]#[N:13].[NH2:14][C:15]1C(C#N)=CC(C(F)(F)F)=CC=1Br>C(OCC)(=O)C>[C:15]([C:7]1[CH:6]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:4]=[C:3]([C:12]#[N:13])[C:2]=1[NH2:1])#[N:14]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Reactant: N#Cc1cc(C(F)(F)F)cc(Br)c1N
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)cc(C#N)c1N
Temperature: 170 °C

Procedure:
A stirred suspension of copper (I) cyanide (3g) and 4-amino-3-bromo-5-cyano-trifluoromethylbenzene (from Preparation 4) (6g) in dry, distilled N-methyl pyrollidinone (50ml) was heated to 170° C. for 16 hours. After cooling to ambient temperature, the reaction mixture was poured into water and ammonium hydroxide, filtered, and the filtrate extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulphate and the solvent evaporated under reduced pressure, to give a yellow oil. Chromatography on silica gel using petroleum ether (boiling range 60-80° C.) containing ethyl acetate (16% by volume) gave 2,6-dicyano-4-trifluoromethyl aniline as a pale yellow solid.