Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][C:16]=1[Cl:26].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Cl:26][C:16]1[CH:17]=[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][C:15]=1[NH:14][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1)=[O:13]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: O=C(O)c1nccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(NC(=O)c2nccc3ccccc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 55.7 %

Procedure:
In DMF (15 ml) were dissolved 1-isoquinolinecarboxylic acid (1.00 g, 5.77 mmol), methyl 4-amino-3-chlorophenylacetate (1.23 g, 6.16 mmol), HOBt (0.16 g, 1.15 mmol), and DMAP (0.14 g, 1.15 mmol). To the resulting solution was added EDC HCl (1.33 g, 6.93 mmol), followed by stirring at room temperature for 14 hours. The reaction mixture was poured into water (40 ml). The crystals precipitated were collected by filtration under reduced pressure, washed with water and ether, dried under reduced pressure to give methyl (3-chloro-4-((1-isoquinolinylcarbonyl)amino)phenyl)acetate (1.14 g, 56%) as a brown solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[C:5]([Br:14])[CH:4]=1.N1C=CN=C1.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.CCOCC>[Si:20]([O:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[C:5]([Br:14])[CH:4]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cc(Br)cc(CO)n1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1cc(Br)cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)n1
Reaction time: 3 h
Yield: 125.4 %

Procedure:
Predried ethyl 6-hydroxymethyl-4-bromopyridine-2-carboxylate (1.4 g, 5 4 mmol) and imidazole (1.1 g, 6.5 mmol) were dissolved in dry DMF (1.7 mL). TBDPS-chloride (1.78 g, 6.5 mmol) was added portionwise, and the reaction was allowed to proceed for 3 h at r.t. The reaction mixture was diluted with Et2O (50 mL) and washed with water and sat. NaHCO3. The organic phase was dried over Na2SO4 and evaporated to dryness. Purification on silica gel (petroleum ether, by 40-60° C./ethyl acetate 5:2) yielded 2.5 g (92%) of the title compound.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[C:15]2[CH:21]=[CH:20][N:19]([Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:16]2=[N:17][CH:18]=1.[Sn:29](I)([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33]>C1COCC1.C(OCC)(=O)C>[C:25]([Si:22]([CH3:24])([CH3:23])[N:19]1[C:16]2=[N:17][CH:18]=[C:13]([Sn:29]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:30][CH2:31][CH2:32][CH3:33])[CH:14]=[C:15]2[CH:21]=[CH:20]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CCCC[Sn](I)(CCCC)CCCC
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(Br)cnc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc2c(ccn2[Si](C)(C)C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 115.8 %

Procedure:
To 2.5 M n-BuLi in hexane (0.67 mL, 1.69 mmol) in THF (5 mL), cooled to −78° C., was added a solution of 26 (0.25 g, 0.80 mmol) in THF (1.0 mL) dropwise. The solution was stirred at −78° C. for 10 min then a solution of Bu3SnI (446 mg, 0.96 mmol) in THF (0.5 mL) was added in one portion. The reaction mixture was stirred at −78° C. for 1 h then at room temperature for 2 h, then poured onto a mixture of ethyl acetate/saturated aq. NaHCO3. The aqueous phase was extracted with more ethyl acetate (2×). The combined organic solutions were dried (MgSO4) and concentrated to give stannane 42 as a light orange oil (483 mg, 115%); 1H NMR (400 MHz, CDCl3) δ 0.71 (s, 6H), 0.98 (t, J=7.4 Hz, 9H), 1.02 (s, 9H), 1.15-1.70 (m, 18H), 6.56 (d, J=3.5 Hz, 1H), 7.26 (d, J=3.5 Hz, 1H), 8.01 (d, J=1.4 Hz, 1H), 8.33 (d, J=1.4 Hz, 1H).
Reaction SMILES: ClC1C=CC(C2C3C=CC(N)=NC=3C3C(C)=NOC=3C[N:14]=2)=CC=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]3[C:49](F)=[N:48][CH:47]=[CH:46][C:33]=3[C:34]3[C:44]([CH3:45])=[N:43][O:42][C:35]=3[C@H:36]([CH2:38][C:39]([NH2:41])=[O:40])[N:37]=2)=[CH:27][CH:26]=1.ClC1C=CC2C(C3C=CC(Cl)=CC=3)=NCC3ON=C(C)C=3C=2N=1>CS(C)=O.CCO>[NH2:14][C:49]1[C:32]2[C:31]([C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=3)=[N:37][C@@H:36]([CH2:38][C:39]([NH2:41])=[O:40])[C:35]3[O:42][N:43]=[C:44]([CH3:45])[C:34]=3[C:33]=2[CH:46]=[CH:47][N:48]=1
Reactant: Cc1noc2c1-c1ccnc(F)c1C(c1ccc(Cl)cc1)=N[C@H]2CC(N)=O
Reactant: Cc1noc2c1-c1nc(N)ccc1C(c1ccc(Cl)cc1)=NC2
Agent: Cc1noc2c1-c1nc(Cl)ccc1C(c1ccc(Cl)cc1)=NC2
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1noc2c1-c1ccnc(N)c1C(c1ccc(Cl)cc1)=N[C@H]2CC(N)=O

Procedure:
A procedure similar to 5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepin-2-amine was followed, except that a solution of 2-((4S)-6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-4-yl)acetamide in DMSO was used instead of a solution of 2-chloro-5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine in EtOH. LC/MS m/z 382 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J=5.19 Hz, 1H), 7.67 (br. s, 1H), 7.38 (td, J=2.30, 8.70 Hz, 2H), 7.33 (td, J=2.30, 8.70 Hz, 2H), 7.04 (br. s, 1H), 6.95 (d, J=5.19 Hz, 1H), 5.89 (br. s, 2H), 4.40 (dd, J=6.54, 8.00 Hz, 1H), 3.27 (dd, J=8.00 Hz, 15.60, 1H), 3.11 (dd, J=6.65, 15.58 Hz, 1H), 2.49 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:17][CH2:16]2)=[CH:11][C:10]=1[Cl:30])C1C=CC=CC=1.Cl>C(O)(=O)C>[ClH:30].[Cl:30][C:10]1[CH:11]=[C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:17][CH2:16]2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Clc1cc(N2CCN(CCCC3CCCCC3)CC2)ccc1OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: Oc1ccc(N2CCN(CCCC3CCCCC3)CC2)cc1Cl
Reaction time: 2 h
Yield: 143.7 %

Procedure:
1-(4-Benzyloxy-3-chlorophenyl)-4-(3-cyclohexylpropyl)-piperazine (1.21 g) was suspended in acetic acid (6.0 mL), and to the suspension conc. hydrochloric acid (2.83 mL) was added, followed by 2 hours' heating under reflux. Allowing the system to cool off, the solvent was distilled off under reduced pressure, and the remaining crystals were washed with acetone and dried under reduced pressure at 60° C., to provide 2-chloro-4-[4-(3-cyclohexylpropyl)piperazin-1-yl]-phenol hydrochloride (760 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:25]O)=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:47]>>[CH3:1][C:2]1[NH:3][C:4]([CH2:25][Cl:47])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1Cl
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1=C(C)NC(CCl)=C(C(=O)OCC)C1c1ccccc1Cl

Procedure:
A mixture of diethyl 2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (379.8 mg) and triphenylphosphine (314.7 mg) in carbon tetrachloride (5 ml) was refluxed for 3.5 hours. After the solvent was removed, the residue was dried under reduced pressure to give diethyl 2-methyl-4-(2-chlorophenyl)-6-chloromethyl-1,4-dihydropyridine-3,5-dicarboxylate. To this residue in 99% ethanol (10 ml) was added N-methylpiperazine (200 mg) and the solution was stirred at room temperature for 50 hours. Ethanol was removed from the reaction mixture and to the residue was added water. The mixture was extracted with ethyl acetate. After washing the extract with water, the extract was back-extracted with dilute hydrochloric acid. The aqueous layer was washed with diethyl ether, basified with an aqueous solution of sodium bicarbonate, and then extracted with ethyl acetate. The extract was washed with water, dried and then concentrated to give crude crystals (115.2 mg) of diethyl 2-methyl-4-(2-chlorophenyl)-6-(N-methylpiperazin-1-yl-methyl)-1,4-dihydropyridine-3,5-dicarboxylate. The crude crystals were recrystallized from a mixture of ethanol and diethyl ether to give colorless needles, m.p. 179° to 180° C.
Reaction SMILES: [C:1](=[O:23])([O:21][CH3:22])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([C:10]#[C:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:5][C:4]=1[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[F:42][C:43]([F:59])([F:58])[O:44][C:45]1[CH:46]=[CH:47][C:48]2[O:53][CH:52]([C:54](O)=[O:55])[CH2:51][NH:50][C:49]=2[CH:57]=1>CC1CCCO1.C(OCC)(=O)C>[C:1](=[O:23])([O:21][CH3:22])[O:2][C:3]1[CH:8]=[C:7]([NH:9][C:54]([CH:52]2[O:53][C:48]3[CH:47]=[CH:46][C:45]([O:44][C:43]([F:59])([F:42])[F:58])=[CH:57][C:49]=3[NH:50][CH2:51]2)=[O:55])[C:6]([C:10]#[C:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:5][C:4]=1[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C(O)C1CNc2cc(OC(F)(F)F)ccc2O1
Reactant: COC(=O)Oc1cc(N)c(C#CCN(C)C)cc1C1CCCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: COC(=O)Oc1cc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(C#CCN(C)C)cc1C1CCCC1

Procedure:
5-Amino-2-cyclopentyl-4-(3-(dimethylamino)prop-1-ynyl)phenyl methyl carbonate (150 mg, 0.47 mmol) was dissolved in 2-methyltetrahydrofuran (3 mL) and T3P (754 mg, 705 μL of 50% w/w, 1.18 mmol). 6-(Trifluoromethoxy)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (125 mg, 0.47 mmol) was added portion-wise over 30 min. After 3 h the reaction was diluted with ethyl acetate, washed with 10% saturated NaHCO3 (2×20 mL) and brine. The solution was dried over Na2SO4, filtered, and dried down to an orange solid. Purification by silica gel chromatography (1% methanol/dichloromethane) provided 2-cyclopentyl-4-(3-(dimethylamino)prop-1-ynyl)-5-(6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)phenyl methyl carbonate as a colorless oil. LC/MS m/z 562.2 [M+H]+. The oil was dissolved in methanol (3 mL) and treated with NaOH (0.5 mL of 5 M, 2.4 mmol) and stirred for 5 min. Water (5 mL) and saturated NaHCO3 (2 mL) were added until a white precipitate formed. The product was extracted into ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide N-(4-cyclopentyl-2-(3-(dimethylamino)prop-1-ynyl)-5-hydroxyphenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide as a off-white solid (90 mg, 34% yield). LC/MS m/z 504.2 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 10.72 (s, 1H), 10.16 (s, 1H), 9.25 (s, 1H), 7.53 (s, 1H), 7.25 (s, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 6.52-6.49 (m, 1H), 4.91 (dd, J=3.0, 6.3 Hz, 1H), 4.32 (t, J=3.8 Hz, 2H), 3.54 (dd, J=3.0, 12.2 Hz, 1H), 3.42 (dd, J=6.3, 12.3 Hz, 1H), 3.14 (quin, J=8.4 Hz, 1H), 2.85 (d, J=4.4 Hz, 6H), 1.91 (m, 2H), 1.72 (m, 2H), 1.63-1.60 (m, 2H), 1.48 (m, 2H).
Reaction SMILES: [C:1]([CH:3]1[CH2:5][N:4]1[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:15](OC)=[O:16])=[N:11][C:12]=1[O:13][CH3:14])#[N:2].[BH4-].[Na+].[Cl-].[Li+]>O1CCCC1>[OH:16][CH2:15][C:10]1[N:11]=[C:12]([O:13][CH3:14])[C:7]([CH2:6][N:4]2[CH2:5][CH:3]2[C:1]#[N:2])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CN2CC2C#N)c(OC)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1nc(CO)ccc1CN1CC1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
247 mg. (1 mmol) methyl 5-[(2-cyano-1-aziridinyl)-methyl]-6-methoxypyridine-2-carboxylate (see Example 1) are dissolved in 10 ml. of anhydrous tetrahydrofuran and the solution is mixed with 74 mg. (2 mmol) sodium borohydride and 84 mg. (2 mmol) lithium chloride. After stirring for 12 hours at ambient temperature, the same amounts of sodium borohydride and lithium chloride are again added and, after a further 12 hours, the reaction mixture is mixed with 5 ml. water, evaporated and the residue taken up in ethanol and filtered. The filtrate is evaporated, the residue is taken up in acetone, filtered and evaporated. The residue is purified over a silica gel column (elution agent: acetone/toluene 1:3 v/v) (Rf value about 0.3) to give 120 mg. (55% of theory) of the desired product; m.p. 68°-70° C.
Reaction SMILES: C1COC2C=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=4)[N:13]=3)=CC=2O1.ClC1N=C(NCC[S:37][CH2:38][C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[Cl:46])C(F)=CN=1.NC1C=C(O)C=CC=1>>[Cl:46][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]([F:45])[C:39]=1[CH2:38][S:37][CH2:6][CH2:5][NH:11][C:12]1[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[N:13]=1
Reactant: Fc1cnc(Cl)nc1NCCSCc1c(F)cccc1Cl
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(F)c(NCCSCc3c(F)cccc3Cl)n2)c1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-[2-[(2-chloro-6-fluorobenzyl)thio]ethyl]-5-fluoro-4-pyrimidineamine and 3-aminophenol were reacted to yield N4-[2-[(2-chloro-6-fluorobenzyl)thio]ethyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (methyl sulfoxide-d6): δ 9.76 (bs, 1H), 9.42 (bs, 1H), 8.70 (bs, 1H), 8.02 (d, 1H, J=5.1 Hz), 7.33-7.30 (m, 2H), 7.24-7.18 (m, 1H), 7.08-6.96 (m, 2H), 6.42 (d, 1H, J=4.6 Hz), 3.82 (d, 2H, J=1.2 Hz), 3.68-3.61 (m, 2H), 2.77 (t, 2H, J=7.2 Hz); LCMS: ret. time: 23.00 min.; purity: 93%; MS (m/e): 424 (MH+).
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3]([O:5][CH3:6])=[O:4].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2OC(=O)[S:21][N:20]=2)=[CH:15][CH:14]=1)#[N:12]>ClC1C=CC=CC=1Cl>[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:1]([C:7]([O:9][CH3:10])=[O:8])[S:21][N:20]=2)=[CH:15][CH:14]=1)#[N:12]
Reactant: COC(=O)C#CC(=O)OC
Reactant: N#Cc1ccc(-c2nsc(=O)o2)cc1
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1snc(-c2ccc(C#N)cc2)c1C(=O)OC

Procedure:
Dimethyl acetylenedicarboxylate (42.63 g, 0.4 mol) and 5-(p-cyanophenyl)-1,3,4-oxathiazol-2-one (20.42 g, 0.1 mol) were heated at reflux in o-dichlorobenzene for 10 hours. Volatile materials were removed under reduced pressure (1 mm). The red-brown residue contained at least three contaminants (g.c.) which were removed by crystallization from methanol. Four recrystallizations resulted in 18.1 g (0.0598 mol, 59.8%) of light yellow solid, m.p. 134°-135°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][Si](C)(C)C.[F-].[Cs+]>C(#N)C.O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[CH:11]
Reactant: COC(=O)c1ccccc1C#C[Si](C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: C#Cc1ccccc1C(=O)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
To a solution of 2-trimethylsilanylethynyl-benzoic acid methyl ester (540 mg, 2.32 mmol) in acetonitrile/water (20 mL/5 mL) is added cesium fluoride (1.41 g, 9.30 mmol). The reaction is stirred at room temperature. After 4 h, the reaction is concentrated and the residue is partitioned between EtOAc (100 mL) and 0.2N HCl (30 mL). The aqueous layer is extracted with EtOAc (100 mL) and the combined organic layers are washed with brine, dried (MgSO4), filtered, and concentrated. The residue is chromatographed eluting with 0 to 5% EtOAc/Hexanes to yield the title compound (358 mg, 96%). GC/MS: 160.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:9]=[C:8]([Cl:10])[C:6]([NH2:7])=[C:5]([Cl:11])[CH:4]=1.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[Br:2][C:3]1[CH:9]=[C:8]([Cl:10])[C:6]([NH:7][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[C:5]([Cl:11])[CH:4]=1
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1c(Cl)cc(Br)cc1Cl
Temperature: 40 °C
Reaction time: 28 h
Yield: 96.6 %

Procedure:
12.0 g (50.0 mmol) of 4-bromo-2,6-dichloroaniline hydrochloride was dissolved in 50 mL of pyridine, 9.90 mL (80.0 mmol) of pivaloyl chloride and 0.61 g (5.0 mmol) of N,N-dimethylaminopyridine were added and the mixture was stirred at 40° C. for 28 hours. Thereafter, substantially the same manner as that in Reference Example (1) was repeated to give 15.7 g of 4-bromo-2,6-dichloro-N-pivaloylaniline (yield: 97%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([SH:26])[CH:17]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.CCN(C(C)C)C(C)C.Br[CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44].[NH4+].[Cl-]>C(#N)C.CCOC(C)=O>[CH3:46][O:45][C:43](=[O:44])[CH2:42][CH2:41][S:26][C:18]1[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=[C:16]([C:15](=[O:27])[N:14]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[O:29][CH3:30])[CH3:28])[CH:17]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(S)cc(C(F)(F)F)c1
Reactant: COC(=O)CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cc(C(=O)N(C)c2cnccc2-c2ccc(F)cc2OC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
To a suspension of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-3-mercapto-N-methyl-5-(trifluoromethyl)benzamide (0.2 g, 458 μmol, example 216, intermediate a) in acetonitrile (4 mL) were added DIPEA (118 mg, 160 μL, 917 μmol) and methyl 3-bromopropanoate (91.8 mg, 60.0 μL, 550 μmol) and the clear and colorless solution was stirred at room temperature for 2.25 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (0.178 g; 74%). MS (ESI): m/z=523.13 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:31][C:32]1[C:40]2[C:35](=[CH:36][C:37]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:39]=2)[N:34]([CH3:45])[CH:33]=1>C1COCC1.CC(C)=O>[Br:31][C:32]1[C:40]2[C:35](=[CH:36][C:37]([S:41]([N:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=3[O:2][CH3:1])[C:7]3[S:11][N:10]=[CH:9][N:8]=3)(=[O:42])=[O:43])=[CH:38][CH:39]=2)[N:34]([CH3:45])[CH:33]=1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: Cn1cc(Br)c2ccc(S(=O)(=O)Cl)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Reaction time: 0.08 h

Procedure:
A 1 L round bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (10.36 g, 41.2 mmol) and THF (190 ml) to give a clear, pale-yellow solution. The flask was cooled to −78° C. in a dry ice and acetone bath, then lithium bis(trimethylsilyl)amide (1M in THF) (43.1 ml, 43.1 mmol) was added dropwise. The cooling bath was removed for 10 min, which led to the formation of a clear, orange-colored solution. The flask was placed back in the cooling bath for 5 min, then a solution of 3-bromo-1-methyl-1H-indole-6-sulfonyl chloride (11.56 g, 37.5 mmol) in minimal THF was added dropwise via cannula. Following the addition, the cooling bath was removed and the reaction was stirred for two hours. The reaction mixture was diluted with a saturated aq. ammonium chloride solution and water, and extracted with EtOAc (2×). The aq. layer was filtered to give some desired product as a pink solid. The filtrate was again extracted with EtOAc, and the organic extracts were combined. The combined solution was dried over sodium sulfate, filtered, and concentrated. The residue was triturated with EtOAc, and the resulting solid was collected via filtration to give a second crop of desired product. The filtrate was absorbed onto silica gel, and the impregnated silica gel was eluted onto a silica gel column (0 to 100% EtOAc/Heptane). The material thus obtained was still impure, so it was further purified by chromatography on silica gel (0 to 10% EtOAc/DCM) to give a third crop of desired product. The three crops were combined to afford 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (16.47 g, 31.5 mmol, 84% yield) as a light pink solid. 1H NMR (400 MHz, DMSO-d6) δ=8.34 (s, 1 H), 8.05 (dd, J=0.6, 1.6 Hz, 1 H), 7.95 (s, 1 H), 7.66-7.52 (m, 2 H), 6.95 (d, J=8.4 Hz, 1 H), 6.47-6.26 (m, 2 H), 5.12 (s, 2 H), 3.88 (s, 3 H), 3.69 (s, 3 H), 3.66 (s, 3 H). m/z (ESI) 545.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=1)[CH2:16][CH:13]1[CH2:15][CH2:14]1)=[O:6]
Reactant: COc1cccc(C(=O)O)c1Cl
Reactant: NCC(CC1CC1)c1cnc(C(F)(F)F)nc1
Product: COc1cccc(C(=O)NCC(CC2CC2)c2cnc(C(F)(F)F)nc2)c1Cl

Procedure:
From 2-chloro-3-methoxybenzoic acid and 3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine. LCMS (MH+): m/z=414.0, tR (minutes, Method F)=2.53
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:9]([Cl:17])=[N:10][CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=O.CN(C=O)C.[NH2:23][C:24](=[N:36]O)[C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([F:35])[CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1>[Cl:7][C:8]1[CH:16]=[C:12]([C:13]2[O:15][N:36]=[C:24]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([F:35])[CH:26]=3)[N:23]=2)[CH:11]=[N:10][C:9]=1[Cl:17]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2noc(-c3cnc(Cl)c(Cl)c3)n2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (507.70 μL; 6 mmol) was added to suspension of 5,6-dichloronicotinic acid (FLUKA; 36000-10G; 384 mg; 2 mmol) and DMF (15.40 μL; 0.20 mmol) in DCM (30 mL) and the resulting mixture was stirred at RT for 1 hour. The solution was then evaporated to dryness. The residue was dissolved in THF (5 mL) and added dropwise to a mixture of Intermediate 1 (424.36 mg; 2 mmol), DIEA (1.03 mL; 6 mmol) in THF (5 mL). The reaction mixture was heated in the microwave at 150° C. for 30 min. When cool to RT the solid was filtered, rinsed with ACN, dissolved in DCM and washed with water. The organic layer was then dried over magnesium sulfate, filtered and concentrated to afford the title compound as a slightly yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ 9.18-9.17 (m, 1H), 8.90-8.89 (m, 1H), 8.17-8 (m, 3H), 3.91 (s, 3H). 19F NMR (DMSO-d6, 300 MHz) δ-108.7 ppm. HPLC (Method A) Rt 5.19 min (Purity: 98.0%).