Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:21])[O:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)=[O:8])[CH3:2].[CH3:23][Sn](C)(C)C>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:21])[O:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14]([CH3:23])[CH:13]=2)=[O:8])[CH3:2]
Reactant: CCOC(=O)CNC(=O)c1c(O)c2ccc(Br)cc2oc1=O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1c(O)c2ccc(C)cc2oc1=O
Temperature: 120 °C
Yield: 61.7 %

Procedure:
A mixture of [(7-bromo-4-hydroxy-2-oxo-2H-chromene-3-carbonyl)-amino]-acetic acid ethyl ester (212 mg, 0.563 mmol), tetramethyltin (0.158 mL, 1.14 mmol) and Pd(PPh3)2Cl2 (20 mg, 0.029 mmol) in N,N-dimethylformamide (2 mL) was heated in a 120° C.-oil bath under nitrogen for 1 h; then cooled, diluted with ethyl acetate, washed with water, saturated NaCl solution, and ethyl acetate phase was dried over Na2SO4, filtered, concentrated and column purified to give desired product (106 mg). ESI (m/z): 306 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH:12](I)([CH3:14])[CH3:13].O>CN(C=O)C>[CH:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([CH3:14])[CH3:13]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 42.4 %

Procedure:
The title compound was prepared according to general procedure A described in Scheme 1. A solution of indole (5 g, 43 mmol) in DMF (60 mL) at to 0° C. was treated with NaH (60% in mineral oil, 3.4 g, 86 mmol) in 4 portions providing a slurry that was gradually warmed to RT over a 30 min period. Isopropyl iodide (1.1 g, 64 mmol) was added to the reaction mixture at RT and the mixture was stirred for 14 h. The reaction mixture was then treated with H2O (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with sat. NaHCO3 (1×50 mL), H2O (1×50 mL) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude material was purified on silica gel (Biotage, 0-10% EtOAc/Hexanes, 30 min.) to provide N-isopropylindole as a colorless oil (2.9 g, 43% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:30][CH2:29][CH2:28][N:12]2[C:13]=1[C:14]1[N:19]=[N:18][C:17]([NH:20][NH:21][C:22]([C:24]2([CH3:27])[CH2:26][CH2:25]2)=O)=[CH:16][CH:15]=1.S(Cl)(Cl)=O>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:30][CH2:29][CH2:28][N:12]2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:22]([C:24]3([CH3:27])[CH2:26][CH2:25]3)=[N:21][N:20]=2)[N:19]=1
Reactant: CC1(C(=O)NNc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn2)CC1
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: CC1(c2nnc3ccc(-c4c(-c5ccc(F)cc5F)nc5n4CCC5)nn23)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 58.1 %

Procedure:
A 125 mL flask was charged with N′-(6-(2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridazin-3-yl)-1-methylcyclopropanecarbohydrazide (0.458 g, 0.614 mmol, prepared using General Procedure AR from Example #35, Step E with 1-methylcyclopropanecarboxylic acid) and 1,4-dioxane (20 mL) to give a brown suspension. To the suspension, thionyl chloride (0.3 mL, 4.11 mmol) was added and the mixture was stirred at about 80° C. After about 4 h, the reaction was concentrated under reduced pressure. The residue was redissolved in DCM and washed with saturated aqueous Na2CO3. The organic solution was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography using MeOH/DCM (gradient; 0:100 to 10:90) to give the title compound (0.140 g, 58% yield): LC/MS (Table 1, Method a) Rt=2.28 min; MS m/z: 393.3 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][C:14]([CH3:16])=[O:15].[OH-].[Na+].O>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:13][C:14](=[O:15])[CH:16]=[CH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccc2ccccc2c1)C=Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.4 %

Procedure:
2-Naphthaldehyde (24, 1.56 g, 10.0 mmol) and acetone (19, 0.37 ml, 5.0 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.60 g, 15.0 mmol) and water (10 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol to give 1.16 g (69%) of a yellow solid: mp 244-246° C. [expected mp 243-244° C.]; 1H NMR: δ 7.23 (d, 2H, J=15.9 Hz), 7.52 (m, 4H), 7.83 (m, 8H), 7.93 (d, 2H, J=15.9 Hz), 8.03 (s, 2H); 13C NMR: δ 123.6, 125.7, 126.7, 127.3, 127.8, 128.6, 128.7, 130.5, 132.3, 133.3, 134.3, 143.1, 190.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8](Cl)=[N:7]2.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.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>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:7]2
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2nc1Cl
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: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)Nc1nc2c(Br)cccc2nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 17.5 h
Yield: 61.6 %

Procedure:
A suspension of 8-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine (Example 304a (˜2.5:1 mixture with 5-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine); 119.0 mg, 0.378 mmol), phenylboronic acid (Aldrich; 46.1 mg, 0.378 mmol), Na2CO3 (200 mg, 1.891 mmol), and Pd(PPh3)4 (Strem Chemicals, Inc.; 21.85 mg, 0.019 mmol) in a mixture of MeCN (3.0 mL) and water (1.000 mL) was stirred under argon at 80° C. for 17.5 h. The reaction mixture was cooled to RT and concentrated onto silica gel. Chromatographic purification (silica gel, 0-10% EtOAc/hexanes) furnished 8-bromo-N-(tert-butyl)-3-phenylquinoxalin-2-amine (83.0 mg, 0.233 mmol, 62% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.85 (1H, dd, J=4.5, 1.2 Hz), 7.83 (1H, dd, J=5.1, 1.4 Hz), 7.67-7.72 (2H, m), 7.51-7.59 (3H, m), 7.20 (1H, t, J=7.8 Hz), 5.23 (1H, br. s.), 1.57 (9H, s). m/z (ESI, +ve) 355.9/358.0 (M+H)+.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:17])[C:9]1=[O:18])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:17])[C:9]1=[O:18]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2c(Cl)cccc2C1=O
Solvent: CO
Solvent: ClCCl
Product: O=CCC1Cc2c(Cl)cccc2C1=O
Reaction time: 1.5 h
Yield: 97 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 90 minutes while stirring through a solution, cooled to -70°, of 15.1 g of (RS)-2-(2-buten-1-yl)-4-chloro-1-indanone in 200 ml of anhydrous dichloromethane and 40 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 7.55 ml of dimethyl sulfide the mixture was stirred at room temperature for 20 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 200 ml of dichoromethane and, after the addition of 25 ml of water and 25 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 200 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 100 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 120 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 13.9 g (97%) of (RS)-2-(2-oxoethyl)-4-chloro-1-indanone were obtained as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:48])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[CH:17](O)[CH2:16][CH:15]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:14]2[CH:27]=[CH:28][CH:29]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH:30]([CH3:35])[CH2:31][C:32]#[C:33][CH3:34])[C:8]=1[O:44][CH2:45][O:46][CH3:47].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:75]>CC#N>[CH3:1][O:2][C:3](=[O:48])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[CH:17]([Cl:75])[CH2:16][CH:15]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:14]2[CH:27]=[CH:28][CH:29]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH:30]([CH3:35])[CH2:31][C:32]#[C:33][CH3:34])[C:8]=1[O:44][CH2:45][O:46][CH3:47]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC#CCC(C)C(C=CC1C(O[Si](C)(C)C(C)(C)C)CC(O)C1c1cccc(CCCC(=O)OC)c1OCOC)O[Si](C)(C)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CC#CCC(C)C(C=CC1C(O[Si](C)(C)C(C)(C)C)CC(Cl)C1c1cccc(CCCC(=O)OC)c1OCOC)O[Si](C)(C)C(C)(C)C
Reaction time: 12 h
Yield: 82 %

Procedure:
A mixture of 4-(3-{3-(tert-butyl-dimethyl-silanyloxy)-2-[3-(tert-butyl-dimethyl-silanyloxy)-4-methyl-oct-1-en-6-ynyl]-5-hydroxy-cyclopentyl}-2-methoxymethoxy-phenyl)-butyric acid methyl ester of 506 mg (0.72 mmol), triphenyl phosphine (350 mg, 1.34 mmol), CH3CN (6 ml), pyridine (112 mg, 1.42 mmol), and CCl4 (240 mg, 1.55 mmol) was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and then, subjected to column chromatography on a silica gel to obtain 4-(3-{3-(tert-butyl-dimethyl-silanyloxy)-2-[3-(tert-butyl-dimethyl-silanyloxy)-4-methyl-oct-1-en-6-ynyl]-5-chloro-cyclopentyl}-2-methoxymethoxy-phenyl)-butyric acid methyl ester (426 mg, yield: 82%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=O)([O-:3])=[O:2].C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:13](=[O:14])[O:15][C:8](=[O:10])[C:7]2=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21

Procedure:
A mixture of 21.1 g of 4-nitrophthalic acid and 50.0 g of acetic anhydride were heated at reflux for 6 hours, following which the acetic acid was removed by distillation at atmospheric pressure. The excess acetic anhydride was removed by distillation at 15 mm Hg pressure with the flask temperature not exceeding 120° C, leaving a quantitative yield of crude 4-nitrophthalic anhydride, m.p. 114°-116° C. The product was recrystallized from chloroform to afford a 93% yield of product, m.p. 123°-124° C, identical to that of Example 1.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[O:8][C:9]1[C:21]([CH:22]2[CH2:24][CH2:23]2)=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[C:11]([F:25])[CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[O:8][C:9]1[C:21]([CH:22]2[CH2:24][CH2:23]2)=[CH:20][C:12]([C:13]([OH:15])=[O:14])=[C:11]([F:25])[CH:10]=1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(C2CC2)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Reaction time: 1 h
Yield: 32.5 %

Procedure:
A solution of tert-butyl 4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoate (0.88 g, 2.54 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (1.9 mL, 25.4 mmol). The resulting mixture was stirred for 1 hour and then concentrated in vacuo. The residue was triturated with methanol to provide the title compound (0.24 g, 32%): 1H NMR (300 MHz, DMSO-d6) δ 12.77 (br s, 1H), 7.26 (d, J=8.5 Hz, 1H), 6.78 (d, J=13.2 Hz, 1H), 4.40-4.34 (m, 1H), 2.39-2.34 (m, 1H), 2.29-2.23 (m, 1H), 1.99-1.88 (m, 1H), 1.85-1.76 (m, 1H), 1.60-1.33 (m, 4H), 1.25-1.03 (m, 3H), 0.88-0.79 (m, 2H), 0.57-0.49 (m, 2H); MS (ES+) m/z 291.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([OH:9])=O)=[CH:4][S:5][CH:6]=1.[CH2:10]([NH2:12])[CH3:11]>O>[CH2:10]([NH:12][C:7]([C:3]1[C:2]([Br:1])=[CH:6][S:5][CH:4]=1)=[O:9])[CH3:11]
Reactant: O=C(O)c1cscc1Br
Reactant: CCN
Solvent: O
Product: CCNC(=O)c1cscc1Br
Yield: 64.5 %

Procedure:
N-Ethyl-4-bromo-3-thiophenecarboxamide was prepared from 4-bromo-3-thiophenecarboxylic acid (7 g, 34 mmol) and 70% ethylamine in water according to steps a and b of Example 248 in 64.5% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[C:23]1([C@@H:29]([NH2:32])[CH2:30][CH3:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:32][C@H:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:30][CH3:31])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: CC[C@H](N)c1ccccc1
Product: CC[C@H](Nc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cn1)c1ccccc1
Temperature: 185 °C
Yield: 40.4 %

Procedure:
Following the procedure described above in Example 51, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile (0.15 g, 0.47 mmol) was reacted with (s)-(−)-1-phenylpropylamine (2.0 mL, 1.86 g, 13.8 mmol) in a sealed vial heated in a microwave reactor at 185° C. for 90 min. The crude product was purified by preparative HPLC and lyophilized to give a fluffy, yellow solid (82 mg, 40.4% yield): 1H NMR (400 MHz, MeOD) δ ppm 0.99 (t, J=7.45 Hz, 3 H) 1.78-2.01 (m, 2 H) 4.58 (t, J=7.20 Hz, 1 H) 6.72 (s, 1 H) 7.14-7.37 (m, 7 H) 7.40 (dd, J=2.53 Hz, 1 H) 8.22 (s, 1 H) 8.81 (s, 1 H); HRMS (ESI+) calcd for C24H19ClFN5 432.13858; found (MH+) 432.1391.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:14]2[CH2:15][CH2:16][NH:17][CH2:18][C:13]2=[N:12][N:11]=1.[C:19]([O:24][C@@H:25]([C:27]1[N:32]=[C:31](Cl)[CH:30]=[CH:29][N:28]=1)[CH3:26])(=[O:23])[CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>C(O)CCC>[C:19]([O:24][C@@H:25]([C:27]1[N:28]=[C:29]([N:17]2[CH2:16][CH2:15][N:14]3[C:10]([C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[N:11][N:12]=[C:13]3[CH2:18]2)[CH:30]=[CH:31][N:32]=1)[CH3:26])(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: c1ccc2sc(-c3nnc4n3CCNC4)nc2c1
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCn3c(nnc3-c3nc4ccccc4s3)C2)n1
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 3-benzothiazol-2-yl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine (prepared according to the method of Example 259, Step C, 170 mg, 0.66 mmol), (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 150 mg, 0.66 mmol), and triethylamine (0.28 mL, 1.98 mmol) in n-butanol (2.2 mL) was heated to reflux overnight, cooled to room temperature, evaporated, and purified by flash column chromatography (1% methanol/chloroform) to give 224 mg (76%) of the title compound of Example 259, Step D as a colorless solid. 1H NMR (CDCl3, 300 MHz) δ 8.37 (d, 1H), 8.08 (d, 1H), 7.97 (d, 1H), 7.57-7.43 (c, 2H), 6.53 (d, 1H), 5.71 (q, 1H), 5.09 (s, 2H), 4.82 (t, 2H), 4.33-4.26 (c, 2H), 2.42 (t, 2H), 1.78-1.64 (c, 2H), 1.61 (d, 3H), 0.99 (t, 3H); MS (APCI) 450 (MH+).
Reaction SMILES: C[Al](C)C.[CH2:5]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]1)[CH2:6][CH2:7][CH3:8].[O:17]1[C:22]2=[C:23]([C:30](OC)=[O:31])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[N:21]2[CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:5]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:30]([C:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[N:21]3[CH2:20][CH2:19][CH2:18][O:17][C:22]=23)=[O:31])[CH2:11][CH2:10]1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCN1CCC(CN)CC1
Reactant: COC(=O)c1c2n(c3ccccc13)CCCO2
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCN1CCC(CNC(=O)c2c3n(c4ccccc24)CCCO3)CC1
Temperature: 10 °C
Yield: 93 %

Procedure:
Method A Toluene (85L) was azeotropically dried in an argon purged reactor, cooled to 10° C. and a solution of trimethylaluminum in toluene (18.57 kg, 16.7% w/w, 43 mole) added. To this at 20 to 24° C. was added a solution of 1-n-butyl-4-piperidinylmethylamine (7.39 kg, 99.4% pure, 42.7 mole) in toluene (22 L) over 43 minutes. Methyl 3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate (9.65 kg, 98.9% pure, 41.3 mole) was added in one portion and the reaction heated to reflux at 112° C. for 4 hours 10 minutes after which time the reaction was judged to be complete by HPLC analysis. 10% Sodium hydroxide solution (52.2 L), prepared from 32% ww sodium hydroxide (24 L) and water (80 L), was added cautiously over 16 minutes at about 60 to 70° C. The resulting mixture was heated to 70 to 80° C. and the aqueous layer separated. The toluene layer was washed with 10% sodium hydroxide (52.2 L) followed twice by water (29 L each wash). The toluene layer was cooled and diluted with hexane fraction (133 L) to crystallise the product. After cooling to about 2° C. overnight the product was collected by filtration, washed on the filter with hexane (21 L) and dried in vacuo at 40° C. overnight to give SB-207266 batch 207266-HP8 (12.26 kg, 94.5% pure, 75.9%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([N:3]([CH2:4][CH3:5])[C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=1)[CH3:2]
Reactant: CCNCC
Reactant: CCOC(=O)c1csc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(N(CC)CC)n1

Procedure:
The reaction described in Preparation 26 was repeated, but using 2.3 g of diethylamine, 4 g of ethyl 2-chlorothiazole-4-carboxylate, 4.2 g of triethylamine, and 15 ml of dimethylformamide, giving ethyl 2-diethylaminothiazole-4-carboxylate as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12]Cl>>[Cl:12][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: ClCl
Product: FC(F)(F)c1ccc(NCl)nc1

Procedure:
The method according to claim 1, wherein 2-amino-5-trifluoromethylpyridine is reacted with chlorine to form 2-chloroamino-5-trifluoromethylpyridine, which is then subjected to a rearrangement reaction in the presence of at least one carboxylic acid selected from the group consisting of formic acid, acetic acid and propionic acid to obtain 2-amino-3-chloro-5-trifluoromethylpyridine.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12]>C(N(CC)CC)C.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.[Cu](I)I>[N+:8]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:12]#[C:11][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cncc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cncc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 159.3 %

Procedure:
To a suspension of 3-bromo-5-nitropyridine (1.0 g, 4.90 mmol), Pd(Ph3P)4 (0.57 g, 0.49 mmol), and copper iodide (0.19 g, 0.98 mmol) in triethylamine (30 mL) was added ethynyltrimethylsilane (1.0 mL, 7.35 mmol) and the reaction was purged with N2. The mixture was stirred at 80° C. for 2 h. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was washed with saturated solutions of NaHCO3 and NaCl. The organic layer was concentrated to afford the crude product (1.72 g) as a light brown solid: ESI MS m/z 221 [C10H12N2O2Si+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]#[N:16])=[C:2]([N:1]=[CH:25][C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:24][CH:23]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1ccc(C(F)(F)F)cc1
Yield: 42 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (100 mg) was suspended in EtOH (4 mL) and alpha,alpha,alpha-Trifluoro-p-tolualdehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain A15 as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (71 mg, 42% yield).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].O>O1CCCC1>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C:16](=[CH2:19])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
2.24 g (0.02 mole) of potassium t-butoxide were added to a solution of 3.55 g (0.01 mole) of 1-t-butoxycarbonyl-3-(p-toluenesulfonyloxymethyl)pyrrolidine [prepared as described in Step (3) above] dissolved in 50 ml of tetrahydrofuran. The mixture was then stirred at room temperature for 3 hours, after which it was poured into water and then extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel eluted with a 5:95 by volume mixture of ethyl acetate and toluene, to give 0.79 g of 1-t-butoxycarbonyl-3-methylenepyrrolidine as a pale yellow liquid.