Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1(Cl)[C:14](=[O:15])[C:13]2[C:12]3[C:7]4=[C:8]([O:16][CH2:17][CH:18]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[N:6]4[C:5]=2[CH2:4][CH2:3]1)[CH:9]=[CH:10][CH:11]=3.C(=O)([O-])[O-].[Li+].[Li+].[Cl-].[Li+]>CN(C=O)C>[Cl:1][C:2]1[C:14]([OH:15])=[C:13]2[C:5]([N:6]3[CH:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:17][O:16][C:8]4[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]3=4)=[CH:4][CH:3]=1
Reactant: O=C1c2c(n3c4c(cccc24)OCC3c2ccccc2)CCC1(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Oc1c(Cl)ccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 120 °C
Yield: 78.6 %

Procedure:
To a mixture of 8,8-dichloro-1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (0.4072 g, 1.09 mmol) in DMF (5 mL) is added lithium carbonate (0.242 g, 3.27 mmol) and lithium chloride (0.143 g, 3.39 mmol). The mixture is heated under an argon atmosphere at 120° C. for 1 h and then partitioned between water and CH2Cl2. The organic layer is washed twice with water (20 mL), dried over magnesium sulfate and concentrated. Column chromatography (50 g silica gel) using ethyl acetate/hexane (20/80) as eluent gave 0.2876 g (78%) of 8-chloro-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[C:20]([O:22][CH3:23])=[O:21])[C:14]([OH:16])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[OH:49][C:50]1[CH:51]=[C:52]([CH:55]=[CH:56][CH:57]=1)[CH2:53][NH2:54].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:13]([C:14]([NH:54][CH2:53][C:52]2[CH:55]=[CH:56][CH:57]=[C:50]([OH:49])[CH:51]=2)=[O:16])=[CH:12][C:11]=1[Br:10]
Reactant: COC(=O)c1ccc(C(=O)O)cc1Br
Reactant: NCc1cccc(O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
Diisopropylethylamine (8.4 mL, 48.2 mmol) was added dropwise to a cooled (˜0° C.) solution of with 3-bromo-4-(methoxycarbonyl)benzoic acid (Example 76; 5.00 g, 19.3 mmol), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (7.31 g, 19.3 mmol), 3-hydroxybenzylamine hydrochloride salt (Example 69; 3.37 g, 21.2 mmol) and 1-hydroxybenzotriazole (2.6 g, 19.2 mmol) in N,N-dimethylformamide (50 mL). After the solution was allowed to stir at ˜0° C. for 1 h, then at room temperature for 4 h, it was concentrated in vacuo (˜1 mm) to remove most of the N,N-dimethylformamide. The residue was partitioned between ethyl acetate and 1N hydrochloric acid solution (200 mL each). The ethyl acetate layer was washed with 1N hydrochloric acid solution (2×100 mL) and the combined aqueous layers were extracted with ethyl acetate (50 mL). The combined ethyl acetate layers were washed with saturated sodium bicarbonate solution (2×100 mL) and brine, then dried (MgSO4), filtered and evaporated under reduced pressure. The solid residue was crystallized from hot ethyl acetate (˜60 mL) and hexanes (15 mL) to give 2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoic acid methyl ester (5.15 g, 73% yield) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]#[N:24]>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]#[N:24]
Reactant: N#CCc1ccccc1I
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1ccccc1CC#N
Yield: 87 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (110 mg, 0.60 mmol) was converted (using 2-iodo-phenylacetonitrile instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=100:0 to 80:20, 156 mg, 87%) which was obtained as a light brown oil. MS: m/e=375.1 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[C:5]([C:11]#[N:12])=[N:6][C:7]([F:10])=[CH:8][N:9]=1)=[N+]=[N-].[H][H]>CO.C(=O)([O-])[O-].[Ca+2].[Pd+2].C(=O)([O-])[O-]>[NH2:1][C:4]1[C:5]([C:11]#[N:12])=[N:6][C:7]([F:10])=[CH:8][N:9]=1
Reactant: [H][H]
Reactant: N#Cc1nc(F)cnc1N=[N+]=[N-]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: N#Cc1nc(F)cnc1N
Yield: 38.6 %

Procedure:
In 5.0 mL of methanol was dissolved 0.24 g of 3-azido-6-fluoro-2-pyrazinecarbonitrile. After adding 0.075 g of lead-poisoned palladium-calcium carbonate at room temperature, hydrogen gas was introduced into the mixture at room temperature under a pressure of 1 atmosphere until the mixture became showing no further adsorption of hydrogen. After filtering off the insoluble matter from the reaction mixture, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: chloroform] to obtain 0.078 g of 3-amino-6-fluoro-2-pyrazinecarbonitrile as a yellow-colored solid product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[C:2]1=[O:11].[H-].[Na+].Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>CN(C=O)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3](=[O:10])[C:2]3=[O:11])[CH2:22][CH2:21]2)=[CH:29][CH:28]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: Fc1ccc(CN2CCN(CCCl)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(CCN2CCN(Cc3ccc(F)cc3)CC2)c2ccccc21
Temperature: 80 °C

Procedure:
1H-Indole-2,3-dione (2.9 g) in dry DMF (5 ml) at 0° C. was treated with sodium hydride (80% dispersion in mineral oil, 600 mg). The mixture was warmed to 40° C. and after 45 minutes a solution of 1-(2-chloroethyl)-4-[(4-fluorophenyl)methyl]piperazine (5.1 g) in dry DMF (8 ml) was added. The reaction mixture was heated at 80° C. for 5 hours and then evaporated under reduced pressure. The residue was recrystallised twice to give 1-[2-[4-[(4-fluorophenyl)methyl]-1-piperazinyl]ethyl]-1H-indole-2,3-dione, m.p. 146°-147° C.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][N:13]=C(OCC)C)(=[O:11])=[O:10].Cl(O)(=O)(=O)=O>O1CCOCC1>[C:1]1([CH3:19])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10]
Reactant: CCOC(C)=NOS(=O)(=O)c1c(C)cc(C)cc1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1COCCO1
Product: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Ethyl N-mesitylsulfonyloxyacetimidate (20 g, 65.7 mmol, 1 eq) was dissolved in 1,4-dioxane (6 ml) and the solution was cooled to 0° C. To the mixture was added dropwise Perchloric acid (10 m), and the reaction mixture was then stirred at 0° C. for 45 minutes. The solution was poured into ice water, and the solid precipitated was filtered and washed with water and dried for 15 minutes in vacuum. The sample was stored in plastic container at −20° C. 1HNMR (400 MHz, DMSO-d6): δ 2.32 (s, 3H), 2.64 (s, 6H), 4.98 (br peak, 2H), 6.99 (s, 2H).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[Cl:17].Cl>[OH-].[K+]>[Cl:17][C:5]1[CH:6]=[CH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:9][C:4]=1[C:3]([OH:18])=[O:2]
Reactant: COC(=O)c1cc(-c2ccc(C)nc2)ccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(-c2ccc(Cl)c(C(=O)O)c2)cn1
Yield: 122.6 %

Procedure:
A solution of 2-chloro-5-(6-methyl-pyridin-3-yl)-benzoic acid methyl ester (146 mg, 0.56 mmol) in methanolic potassium hydroxide (2.24 mL, 1M) was stirred at 80° C. for 16 h. The reaction mixture was acidified (pH 3) with 1N HCl and concentrated in vacuo. The residue was shaken thoroughly with methanol and filtered. The filtrate was concentrated in vacuo to afford the title compound (170 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:52])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=5[O:34][C@H:35]([CH2:37]C=C)[CH3:36])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[C:14]([CH3:40])=[C:13]([CH3:41])[C:12]=2[C@H:42]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[C:43]([O:45][CH3:46])=[O:44])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:48]([O:47][C@@H:42]([C:12]1[C:13]([CH3:41])=[C:14]([CH3:40])[C:15]2=[N:19][C:18]3=[CH:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:52])([O:4][CH2:1][CH:2]=[CH:3][CH2:37][C@H:35]([CH3:36])[O:34][C:27]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:6][CH2:7]1)[C:43]([O:45][CH3:46])=[O:44])([CH3:49])([CH3:51])[CH3:50]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5cc(F)c(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OC/C=C\C[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1

Procedure:
Prepared in 83% yield from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′,5′-difluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate. LCMS (ESI, M+1): 688.80.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C(C1CCC(CNC2C=CC(F)=C(F)C=2)CC1)(C)(C)C.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:23]([CH:20]1[CH2:21][CH2:22][CH:17]([CH2:16][N:15]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:35])=[O:3])=[CH:8][N:9]=2)[CH2:18][CH2:19]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCC(C(C)(C)C)CC2)c2ccc(F)c(F)c2)s1
Agent: CC(C)(C)C1CCC(CNc2ccc(F)c(F)c2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: CC(C)(C)C1CCC(CN(C(=O)Nc2ncc(SCC(=O)O)s2)c2ccc(F)c(F)c2)CC1

Procedure:
The title compound was prepared via {2-[3-(3,4-difluoro-phenyl)-3-(4-tert-butylcyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 4-tert-butyl-cyclohexylmethyl-(3,4-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: C(OC([NH:8][C:9]1[C:17]([O:18][CH3:19])=[N:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C:9]1[C:17]([O:18][CH3:19])=[N:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: COc1nccc(C(=O)O)c1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1nccc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
3-[(T-butoxycarbonyl)amino]-2-methoxyisonicotinic acid (6.6 g, 24.6 mmol) was dissolved in trifluoroacetic acid (10 mL), and stirred at room temperature for 8 hours. The solvent was evaporated off under reduced pressure, and the resulting milky white solid was washed with water and ethanol to obtain a white solid (2.35 g, 56.8%). The mother liquid was again concentrated, and the resulting residue was washed with acetone and hexane to obtain a pale pink solid (1.3 g, 31.4%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]([O:21][C@@H:22]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:23]3[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15][NH:16][C:17]=2[CH:18]([CH3:20])[CH3:19])=[C:8]([CH3:57])[CH:7]=1.[CH2:58]([NH:65][CH2:66][CH2:67][C:68]([NH2:70])=[O:69])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.[I-].[Na+].Cl>C(#N)C.C(O)C>[CH2:58]([N:65]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]([O:21][C@@H:22]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:23]3[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15][NH:16][C:17]=2[CH:18]([CH3:20])[CH3:19])=[C:8]([CH3:57])[CH:7]=1)[CH2:66][CH2:67][C:68](=[O:69])[NH2:70])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: Cc1cc(OCCCCl)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Reactant: NC(=O)CCNCc1ccccc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: Cc1cc(OCCCN(CCC(N)=O)Cc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Temperature: 70 °C
Reaction time: 48 h
Yield: 61.7 %

Procedure:
A mixture of 4-{[4-(3-chloropropoxy)-2-methylphenyl]-methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (1.34 g), 3-benzylaminopropionamide (0.73 g), sodium iodide (0.24 g), ethanol (6 mL) and acetonitrile (6 mL) was stirred at 70° C. for 2 days. To the reaction mixture was added sodium iodide (0.2 g), and the mixture was further stirred at 75° C. for 24 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/5−dichloromethane/methanol=15/1) to give the title compound (0.97 g).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1.[C:15](N1C=CN=C1)([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[S:16]>C(#N)C>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH:11][C:15]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[S:16])[S:10][C:6]=2[CH:5]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2ccc(OC(F)F)cc2s1
Solvent: CC#N
Product: FC(F)Oc1ccc2nc(NC(=S)n3ccnc3)sc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To 6-(difluoromethoxy)benzo[d]thiazol-2-amine (0.5 g, 2.3 mmol) in acetonitrile (15 mL) was added 1,1′-thiocarbonyldiimidazole (0.49 g, 2.8 mmol). The reaction was stirred at 70° C. overnight. The reaction was cooled to room temperature and the precipitate was filtered to yield N-(6-(difluoromethoxy)benzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide (500 mg, 1.53 mmol, 66.3% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.[F:11][C:12]1[CH:13]=[C:14]([NH2:20])[C:15]([NH2:19])=[CH:16][C:17]=1[F:18]>>[Cl:1][C:2]1[C:3]([C:4]2[NH:19][C:15]3[CH:16]=[C:17]([F:18])[C:12]([F:11])=[CH:13][C:14]=3[N:20]=2)=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Nc1cc(F)c(F)cc1N
Product: Fc1cc2nc(-c3cccnc3Cl)[nH]c2cc1F
Temperature: 180 °C
Yield: 48 %

Procedure:
To a suspension of 2-chloro-nicotinic acid (4.10 g, 0.026 mol; CAS Reg. No. 2942-59-8) in polyphosphoric acid (50 g) was added 4,5-difluoro-benzene-1,2-diamine (3.86 g, 0.026 mol; CAS Reg. No. 76179-40-3) and the resulting mixture was heated to 180° C. for 1 h. The reaction mixture was then cooled and neutralized with ice cold 10% aqueous sodium carbonate solution, and then extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue thus obtained was purified by column chromatography over silica gel (25% ethyl acetate/n-hexane) to give the title compound as a brown solid (48%). MS (Turbo Spray): m/z=266.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]#[CH:23])=[N:20][C:19]([N:24]2[CH2:29][CH2:28][N:27]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH2:26][CH2:25]2)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N:36]([C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1)=[N+:37]=[N-:38].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].CCN(C(C)C)C(C)C>CC(O)(C)C.O>[C:11]([O:10][C:9]([N:8]([C:16]1[C:21]([C:22]2[N:38]=[N:37][N:36]([C:39]3[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=3)[CH:23]=2)=[N:20][C:19]([N:24]2[CH2:29][CH2:28][N:27]([S:30]([CH2:33][CH3:34])(=[O:31])=[O:32])[CH2:26][CH2:25]2)=[CH:18][N:17]=1)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: [N-]=[N+]=Nc1ccc(N)cc1
Reactant: C#Cc1nc(N2CCN(S(=O)(=O)CC)CC2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Solvent: O
Product: CCS(=O)(=O)N1CCN(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cn(-c4ccc(N)cc4)nn3)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl N-tert-butoxycarbonyl-N-[5-(4-ethylsulfonylpiperazin-1-yl)-3-ethynyl-pyrazin-2-yl]carbamate (50 mg, 0.1009 mmol) and 4-Azidoaniline hydrochloride (17.32 mg, 0.1009 mmol) were suspended in t-BuOH (1 mL)/Water (1.000 mL). The reaction was treated with (+)-Sodium L-ascorbate (1.999 mg, 0.01009 mmol) followed by CuSO4.5H2O (0.2519 mg, 0.1103 μL, 0.001009 mmol) and the mixture allowed to stir at ambient temperature for 16 hours. The reaction was treated with DIPEA (13.04 mg, 17.57 μL, 0.1009 mmol) and allowed to heat to 40° C. for 5 hours and then cooled to ambient temperature. The mixture was partitioned between EtOAc/NaHCO3 and the aqueous layer extracted with EtOAc (2×), dried (MgSO4), filtered and concentrated. The material was used crude in the next step (quantitative yield assumed). MS (ES+) 630.00
Reaction SMILES: [BH4-].[Na+].C([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=O)C.[CH2:12]([OH:14])[CH3:13]>>[OH:14][CH:12]([C:9]1[CH:8]=[N:7][CH:6]=[CH:11][CH:10]=1)[CH3:13]
Reactant: CC(=O)c1ccccn1
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium borohydride (1.75 g) was added in portions to a stirred solution of acetylpyridine (12.1 g) in ethanol (100 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 20 min, then concentrated under reduced pressure to remove ethanol. The thick residue was diluted with 300 mL of dichloromethane, 25 mL of water and 5 mL of 20% NaOH. The aqueous layer was saturated with sodium chloride, and extracted with ethyl acetate (4×150 mL). The combined organic extracts were dried (MgSO4) and concentrated. Evaporative distillation of the crude oily product (14.0 g) at 1 mm, oven temperature 85°-95° C. gave 11.4 g of 3-(1-hydroxyethyl)pyridine as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][S:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C:25]#[CH:26])[CH:20]=[CH:19][C:17]=3[N:18]=2)(=[O:13])=[O:12])=[CH:5][CH:4]=1.[N:41]([C@@H:44]([CH2:71][C:72]1[CH:77]=[CH:76][C:75]([O:78][CH2:79][CH2:80][O:81][S:82]([C:85]2[CH:91]=[CH:90][C:88]([CH3:89])=[CH:87][CH:86]=2)(=[O:84])=[O:83])=[CH:74][CH:73]=1)[C:45]([N:47]([C@@H:55]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:63][CH:62]=1)[C:56]([O:58][CH3:59])=[O:57])[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:46])=[N+:42]=[N-:43].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu]I>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][S:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[N:43]=[N:42][N:41]([C@@H:44]([CH2:71][C:72]5[CH:73]=[CH:74][C:75]([O:78][CH2:79][CH2:80][O:81][S:82]([C:85]6[CH:91]=[CH:90][C:88]([CH3:89])=[CH:87][CH:86]=6)(=[O:84])=[O:83])=[CH:76][CH:77]=5)[C:45]([N:47]([C@@H:55]([CH2:60][C:61]5[CH:62]=[CH:63][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:65][CH:66]=5)[C:56]([O:58][CH3:59])=[O:57])[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:46])[CH:26]=4)[CH:20]=[CH:19][C:17]=3[N:18]=2)(=[O:13])=[O:12])=[CH:38][CH:37]=1
Reactant: COC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(C(=O)OC(C)(C)C)C(=O)[C@H](Cc1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)cc1)N=[N+]=[N-]
Reactant: C#CCOc1ccc2nc(S(=O)(=O)NC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)sc2c1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(C(=O)OC(C)(C)C)C(=O)[C@H](Cc1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)cc1)n1cc(COc2ccc3nc(S(=O)(=O)NC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)sc3c2)nn1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a stirring solution of N-(bis(4-methoxyphenyl)(phenyl)methyl)-6-(prop-2-ynyloxy)benzo[d]thiazole-2-sulfonamide (83 mg, 0.145 mmol) and the Boc-protected amide 151 (107 mg, 0.145 mmol) in THF (0.7 mL) was added copper(I) iodide (3 mg, 0.0145 mmol) then diisopropylethylamine (28 μL, 0.16 mmol). The mixture was allowed to stir for 2 h at 23° C. then concentrated in vacuo and the crude residue purified by flash chromatgraphy on silica gel using hexanes/ethyl actetate on a Biotage purification system yielding the desired product as a yellow, crystalline solid (145 mg, 82%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[CH:22]=O)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[CH3:28][C:29]([S:32]([NH2:34])=[O:33])([CH3:31])[CH3:30].[BH4-].[Na+].O>O1CCCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.ClCCl>[CH3:28][C:29]([S:32]([NH:34][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=1[S:17]([C:14]1[CH:13]=[CH:12][C:11](/[CH:10]=[CH:9]/[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][CH:2]=2)=[CH:16][CH:15]=1)(=[O:18])=[O:19])=[O:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)S(=O)NCc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)benzaldehyde (Example 176, 500 mg, 1.44 mmol), 2-methyl-2-propanesulfinamide (192 mg, 1.58 mmol) and titanium(IV) ethoxide (0.6 mL, 2.88 mmol) in tetrahydrofuran (7 mL) was heated to reflux for 4 hours. The cooled reaction mixture was partitioned between ethyl acetate and brine. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was taken up in methanol/dichloromethane (3:1, 16 mL) and sodium borohydride (424 mg, 8.64 mmol) added portionwise. After stirring at room temperature for 10 minutes, water and dichloromethane were added. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 50-90% ethyl acetate/isohexane, followed by recrystallisation to give the title compound as a white solid. δH (500 MHz, d6 DMSO): 8.11 (1H, d, J=7.8 Hz), 7.84-7.80 (4H, m), 7.73-7.66 (4H, m), 7.59-7.57 (1H, m), 7.45 (1H, d, J=16.4 Hz), 7.30 (1H, d, J=16.5 Hz), 7.23 (2H, t, J=8.8 Hz), 5.78 (1H, t, J=6.4 Hz), 4.45-4.35 (2H, m), 1.07 (9H, s).