Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC([C@@H]2C(=O)[N:39]([C@@H:42]([C@H:55]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH3:56])[C:43]([NH:45][C:46]3[S:47][CH:48]=[C:49]([C:51](=[O:54])[CH2:52][CH3:53])[N:50]=3)=[O:44])C(=O)N2)=CC=1.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[O:11])[NH:39][C@H:42]([C:43](=[O:44])[NH:45][C:46]1[S:47][CH:48]=[C:49]([C:51](=[O:54])[CH2:52][CH3:53])[N:50]=1)[C@H:55]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[CH3:56])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCCN2CCCCC2)cc1
Reactant: CCC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OC)cc3)C2=O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(OCCN3CCCCC3)cc2)[C@@H](C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-tert-Butoxycarbonylamino-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetic acid (740 mg, ≈1.96 mmol) was dissolved in tetrahydrofuran (30 mL) and (2S,3S)-2-amino-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (250 mg, 0.78 mmol) (prepared as described in example 4) was added followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (180 mg, 0.94 mmol) at 0° C. The reaction mixture was allowed to slowly warm to room temperature. After stirring for 3.5 hours additional (R)-tert-butoxycarbonylamino-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetic acid (320 mg, ≈0.85 mmol) was added to the reaction mixture. After stirring for an additional 1.5 hours an additional aliquot of (R)-tert-butoxycarbonylamino-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetic acid (300 mg, ≈0.82 mmol) was added to the reaction mixture along with additional 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (90 mg, 4.72 mmol). After stirring at room temperature for an additional 1 hour the mixture was partitioned between ethyl acetate and brine, the organic extract was dried over sodium sulfate, concentrated in vacuo and the resulting residue purified by chromatography over silica gel eluted first with ethyl acetate and then gradient eluted with dichloromethane containing from 0 to 10% methanol. {(R)-[(1S,2S)-2-Phenyl-1-(4-propionyl-thiazol-2-ylcarbamoyl)-propylcarbamoyl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-carbamic acid tert-butyl ester was obtained as a white solid (120 mg, 24%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:28])[N:5]([CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)[CH2:13][C:14](=[O:16])[CH3:15])[C:6]2=[O:11].[Cl:29][CH2:30][C:31](Cl)=[O:32]>O1CCCC1>[Cl:29][CH2:30][C:31]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:28])[N:5]([CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)[CH2:13][C:14](=[O:16])[CH3:15])[C:6]2=[O:11])=[O:32]
Reactant: O=C(Cl)CCl
Reactant: CCOc1cc(C(CC(C)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(C)=O)N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)ccc1OC
Yield: 99.6 %

Procedure:
A mixture of 4-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]isoindoline-1,3-dione (0.9 g, 2.34 mmol) and chloroacetyl chloride (0.29 g, 2.57 mmol) in tetrahydrofuran (20 mL) was heated to reflux for 10 minutes. The mixture was concentrated in vacuo to give 2-chloro-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.07 g, 100%); 1H NMR (CDCl3) δ 10.56 (s, 1H), 8.71 (d, J=8.4 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.53 (d, J=7.3 Hz, 1H), 7.09-7.05 (m, 2H), 6.82 (d, J=8.0 Hz, 1H), 5.75-5.69 (dd, J=5.3 and 9.8 Hz, 1H), 4.22 (s, 2H), 4.12 (q, J=7.1 Hz, 2H), 4.04-3.93 (m, 1H), 3.83 (s, 3H), 3.31-3.21 (dd, J=5.2 and 18.0 Hz, 1H), 2.18 (s, 3H), 1.45 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH2:5][CH2:6]O.N1C=CC=CC=1.P(Br)(Br)[Br:17]>C(OCC)C>[Br:17][CH2:6][CH2:5][C:4]#[C:3][Si:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: BrP(Br)Br
Reactant: C[Si](C)(C)C#CCCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: C[Si](C)(C)C#CCCBr
Yield: 117 %

Procedure:
4-Trimethylsilyl-3-butyne-1-ol (14.2 g, 0.1 mol) and 0.2 ml of pyridine were dissolved in 50 ml of diethyl ether under a nitrogen atmosphere. Phosphorus tribromide (3.8 ml, 0.04 mol) was slowly added and the mixture was heated under reflux for 2 hours. Isolation of the product by conventional means yielded 9.6 g of 4-bromo-1-trimethylsilyl-1-butyne as a clear liquid, bp 35°-38° C. at 1 mm Hg.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:12]([O:15][C:16]1[C:17]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:18][C:19]2[O:23][C:22]([CH2:25]I)([CH3:24])[CH2:21][C:20]=2[C:27]=1[C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:14])[CH3:13].[Cl-].[NH4+]>CN(C)C=O>[C:12]([O:15][C:16]1[C:17]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:18][C:19]2[O:23][C:22]([CH2:24][O:1][C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=3)([CH3:25])[CH2:21][C:20]=2[C:27]=1[C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:14])[CH3:13]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CI)O2
Reactant: O=Cc1ccc(O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(COc1ccc(C=O)cc1)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 4.57 g of 4-hydroxybenzaldehyde in 70 ml of N,N-dimethylformamide was added dropwise to an ice-cooled suspension of 1.5 g of 60% oily sodium hydride in 50 ml of N,N-dimethylformamide and the mixture was stirred at room temperature for 30 minutes. Then, the reaction solution was cooled to 0° C. and a solution of 13.2 g of 5-acetoxy-4,6-di-t-butyl-2-iodomethyl-2-methyl-2,3-dihydrobenzofuran synthesized in Example 70-2) in 100 ml of N,N-dimethylformamide was added dropwise, and the mixture was heated under reflux for 6 hours. After cooling, the reaction solution was combined with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with n-hexane containing 20% ethyl acetate to give 6.4 g of 5-acetoxy-4,6-di-t-butyl-2-(4-formylphenoxymethyl)-2-methyl-2,3-dihydrobenzofuran (rotamer mixture) as a colorless oil (yield 48%).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:19]([N:21]1[CH2:109][CH2:108][CH2:107][C@H:22]1[C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:42]([NH:44][C@H:45]([C:48]([NH:50][C@H:51]([C:58]([NH:60][C@H:61]([C:67]([NH:69][CH2:70][C:71]([N:73]1[CH2:106][CH2:105][CH2:104][C@H:74]1[C:75]([NH:77][C@H:78]([C:83]([N:85]1[CH2:103][CH2:102][CH2:101][C@H:86]1[C:87]([NH:89][C@H:90]([C:98]([OH:100])=[O:99])[CH2:91][C:92]1[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=1)=[O:88])=[O:84])[CH2:79][CH2:80][S:81][CH3:82])=[O:76])=[O:72])=[O:68])[CH2:62][CH2:63][CH2:64][CH2:65][NH2:66])=[O:59])[CH2:52][C:53]1[N:57]=[CH:56][NH:55][CH:54]=1)=[O:49])[CH2:46][OH:47])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:33])[NH2:32])=[O:24])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:18])[NH2:17])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[NH:110]([C:132]([O:134]C(C)(C)C)=O)[C@H:111]([C:129]([OH:131])=O)[CH2:112][CH2:113][CH2:114][NH:115][C:116](=[NH:128])[NH:117]S(C1C=CC(C)=CC=1)(=O)=O>>[NH2:10][C@H:11]([C:132]([NH:110][C@H:111]([C:129]([NH:1][C@H:2]([C:8]([NH:10][C@H:11]([C:19]([N:21]1[CH2:109][CH2:108][CH2:107][C@H:22]1[C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:42]([NH:44][C@H:45]([C:48]([NH:50][C@H:51]([C:58]([NH:60][C@H:61]([C:67]([NH:69][CH2:70][C:71]([N:73]1[CH2:106][CH2:105][CH2:104][C@H:74]1[C:75]([NH:77][C@H:78]([C:83]([N:85]1[CH2:103][CH2:102][CH2:101][C@H:86]1[C:87]([NH:89][C@H:90]([C:98]([OH:100])=[O:99])[CH2:91][C:92]1[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=1)=[O:88])=[O:84])[CH2:79][CH2:80][S:81][CH3:82])=[O:76])=[O:72])=[O:68])[CH2:62][CH2:63][CH2:64][CH2:65][NH2:66])=[O:59])[CH2:52][C:53]1[N:57]=[CH:56][NH:55][CH:54]=1)=[O:49])[CH2:46][OH:47])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:32])[NH2:33])=[O:24])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:17])[NH2:18])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:131])[CH2:112][CH2:113][CH2:114][NH:115][C:116](=[NH:128])[NH2:117])=[O:134])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:17])[NH2:18]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CSCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CSCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The resin of Example 26 was further condensed with Boc-Arg(Tos) two times, followed by the same treatment and purification procedure, to give 17 mg of a white powder.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@:10]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[Cl:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1I.C(=O)([O-])[O-].[K+].[K+].[C@H]1(O)CCCC[C@@H]1O.C(O)(C)(C)C>[Cu]I>[Cl:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:14]1[CH2:15][CH2:16][CH2:17][C@@:10]2([C:9](=[O:18])[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]3)[CH2:12][CH2:11]2)[CH2:13]1
Reactant: O=C1N([C@H]2CC[C@H](O)CC2)CC[C@]12CCCNC2
Reactant: Cc1ccc(I)c(Cl)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: O[C@H]1CCCC[C@@H]1O
Solvent: CC(C)(C)O
Product: Cc1ccc(N2CCC[C@]3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)c(Cl)c1
Temperature: 100 °C

Procedure:
A mixture of (5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20 mg, 0.00007 mol) which was prepared using procedures analogous to those described in the synthesis of example 472-a and followed by standard hydrogenation to remove the carbobenzyloxy (Cbz) protecting group and 2-chloro-1-iodo-4-methylbenzene (22.7 mg, 0.0000831 mol), potassium carbonate (20.1 mg, 0.000145 mol), copper(I) iodide (0.6 mg, 0.000003 mol), and (1S,2S)-cyclohexane-1,2-diol (16.1 mg, 0.000138 mol) in tert-butyl alcohol (1.0 mL, 0.010 mol) was heated at 100° C. for 18 h. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 377.1 (M+H)+.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCCCCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: OCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 24 %

Procedure:
The procedure described in example 41 was followed but using 1,5-pentandiol (376 mg, 3.6 mmol) as alcohol instead of cis-2-buten-1,4-diol in the reaction with trityl chloride, which gave the title compound (300 mg, 24%).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:51][O:52][C:53]([C:55]1[C:63]2[N:62]=[C:61]([NH2:64])[NH:60][C:59]=2[CH:58]=[CH:57][CH:56]=1)=[O:54]>CN(C=O)C>[CH3:51][O:52][C:53]([C:55]1[C:63]2[N:62]=[C:61]([NH:64][C:15]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([C:8]#[C:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:14]=3)=[O:17])[NH:60][C:59]=2[CH:58]=[CH:57][CH:56]=1)=[O:54]
Reactant: O=C(O)c1cccc(C#Cc2ccccc2)n1
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2[nH]c(NC(=O)c3cccc(C#Cc4ccccc4)n3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
To a solution of 4.4 g (20 mmol) of 6-phenylethynyl-pyridine-2-carboxylic acid in DMF (30 mL) was added 7.6 g (20 mmol) of HBTU and DIEA (4 mL). The resulted mixture was stirred at room temperature for 10 min, then 4 g (21 mmol) of 2-amino-1H-benzoimidazole-4-carboxylic acid methyl ester (Intermediate A) was added, and stirred at room temperature for 1 h. After usual workup as described in general procedure A, 7 g (88%) of 2-[(6-phenylethynyl-pyridine-2-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid methyl ester was obtained after column chromatography purification eluting with DCM/EtOAc. LCMS: 397 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 8.20 (dd, 1H), 8.13 (dd, 1H), 7.96 (d, 1H), 7.81 (d, 1H), 7.74 (d, 1H), 7.60 (m, 2H), 7.50 (m, 3H), 7.31 (t, 1H), 3.95 (s, 3H) ppm.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([N:17]2[CH2:30][CH2:29][C:20]3[NH:21][C:22]4[C:23]([OH:28])=[CH:24][CH:25]=[CH:26][C:27]=4[C:19]=3[CH2:18]2)=[O:16])=[O:8])[CH2:5][CH2:4]1)#[N:2].Br[CH2:32][C:33]#[N:34].C(=O)([O-])[O-].[K+].[K+].C(O)=O>CN(C=O)C.CC#N.O>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([N:17]2[CH2:30][CH2:29][C:20]3[NH:21][C:22]4[C:23]([O:28][CH2:32][C:33]#[N:34])=[CH:24][CH:25]=[CH:26][C:27]=4[C:19]=3[CH2:18]2)=[O:16])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CCBr
Reactant: N#CC1(NC(=O)[C@@H]2CCCC[C@H]2C(=O)N2CCc3[nH]c4c(O)cccc4c3C2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=CO
Solvent: CN(C)C=O
Product: N#CCOc1cccc2c3c([nH]c12)CCN(C(=O)[C@@H]1CCCC[C@H]1C(=O)NC1(C#N)CC1)C3
Temperature: 80 °C

Procedure:
Following Example 34 (1R,2R)-2-(6-hydroxy-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carbonyl)-cyclohexanecarboxylic acid (1-cyano-cyclopropyl)-amide (102 mg, 0.25 mmol), bromoacetonitrile (50 uL, 0.75 mmol) and potassium carbonate (104 mg, 0.75 mmol) in DMF (5 mL) were heated to 80° C. for 1 h when reaction was ca 60% complete. Preparative HPLC (0.5% HCOOH, CH3CN/H2O gradient) to give a yellow solid (51.9, 47%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[O:6]1[C:10]([C:11]2[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=2)[NH2:14])=[CH:9][N:8]=[CH:7]1>C1COCC1>[O:6]1[C:10]([C:11]2[CH:12]=[C:13]([NH:14][C:2](=[O:3])[O:4][CH3:5])[CH:15]=[CH:16][CH:17]=2)=[CH:9][N:8]=[CH:7]1
Reactant: Nc1cccc(-c2cnco2)c1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)Nc1cccc(-c2cnco2)c1
Temperature: 25 °C
Yield: 42.8 %

Procedure:
Methyl chloroformate (1.67 mL, 21.54 mmol) was slowly added to a 0° C. solution of 3-(oxazol-5-yl)aniline (2.30 gm, 14.36 mmol) and TEA (4.00 mL, 28.70 mmol) in THF (65 mL). The ice bath was removed and the reaction mixture was stirred at rt. After 2.5 h the reaction mixture was concentrated and the residue was partitioned between EtOAc and water. The organic phase was isolated, washed with 1 N HCl (2×) and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography eluting with a gradient of 0-100% EtOAc/Hexanes to give the product, methyl 3-(oxazol-5-yl)phenylcarbamate, (1.34 gm, 6.14 mmol, 43% yield) as a white solid. Anal. Calcd. for C11H10N2O3 m/z 218.1, found: 219.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[Li]CCCC.CN([CH:21]=[O:22])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:21]=[O:22])[CH:11]=[CH:10]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CN(C)C=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1ccc2cc(O)ccc2c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
To a stirred cooled mixture of 6-bromo-2-hydroxynaphthalene (25.3 g, 0.113 mol) in THF (600 mL) at −78° C. was added n-BuLi (2.5 M, 100 mL, 0.250 mol) dropwise. The mixture turned yellow and the temperature rose to −64° C. After ca 5 min a suspension appeared. After addition, the mixture was maintained at −78° C. After 20 minutes, a solution of DMF (28.9 mL, 0.373 mol) in THF (100 mL) was added over 20 minutes. After addition, the mixture was allowed to warm slowly to RT. After 1 hour, the mixture was poured in ice/water (200 mL). To the mixture citric acid was added to a pH of 5. The mixture was stirred for 0.5 hour. Ethyl acetate (200 mL) was added and the organic layer was separated and washed with brine (100 mL), dried over Na2SO4 and concentrated. To the residue was added heptane with 20% ethyl acetate (ca 50 mL) and the mixture was stirred for 1 hour. The mixture was filtered and the solid was washed with ethyl acetate and dried in vacuo to afford 16 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.NC(N)=[S:14].[OH-].[K+]>C(O)C>[SH:14][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: NC(N)=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: FC(F)(F)c1ccc(S)nc1
Temperature: 25 °C
Yield: 38 %

Procedure:
2-chloro-5-trifluoromethylpyridine (13.7 g) was dissolved in ethanol (96 ml), thiourea (5.7 g) was added to the mixture, and the mixture was heated to reflux for 3 hours. After allowing the mixture to be cooled to room temperature, an aqueous solution (19.2 ml) of potassium hydroxide (6.4 g) was added to the mixture, and the mixture was heated to reflux for 1 hour. After allowing the mixture to be cooled to room temperature, diluted aqueous solution of potassium hydroxide (20 ml) was added to the mixture, and the mixture was washed with methylene chloride. With acetic acid, pH of the mixture was adjusted to about 6, and the mixture was extracted with methylene chloride. The mixture was washed with water, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 2-mercapto-5-trifluoromethylpyridine (5.1 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:38]
Reactant: COCC(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from trans-4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A140) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:6][C:7](=[S:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>C1COCC1>[C:1]([C:4]1[CH:5]([C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[N:6]([C:36](=[O:39])[CH2:37][CH3:38])[C:7](=[S:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC(=O)N1C(=S)N(c2cccc(C(F)(F)F)c2)C(C)=C(C(C)=O)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{5-Acetyl-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-4-pyrimidinyl}benzonitrile (Example 1; 100 mg, 0.24 mmol) is dissolved in 3 ml THF. After addition of pyridine (21 mg, 0.26 mmol) and propanoyl chloride (22 mg, 0.24 mmol), the reaction mixture is stirred at room temperature overnight and is then quenched with 10 ml water. After extraction with ethyl acetate (2×10 ml), the organic layer is dried with sodium sulfate, and the crude product is purified via flash chromatography on silica gel using a gradient of cyclohexane/ethyl acetate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]2[C:10]([C:20]3[C:21]([F:41])=[C:22]([N:26](COC)[S:27]([C:30]4[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=4[F:37])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:13]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].Cl.[O:43]1CCOCC1>O.[OH-].[Na+]>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[S:27]([NH:26][C:22]1[C:21]([F:41])=[C:20]([C:10]2[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:43])[CH:8]=3)=[CH:13][N:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:29])=[O:28]
Reactant: COCN(c1cccc(-c2nn(C3CCOCC3)cc2-c2ccnc(C#N)c2)c1F)S(=O)(=O)c1cc(F)ccc1F
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1cc(-c2cn(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{3-[4-(2-cyano-pyridin-4-yl)-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-3-yl]-2-fluoro-phenyl}-2,5-difluoro-N-methoxymethyl-benzenesulfonamide (60 mg, 0.103 mmol) in dioxane (2 mL) concentrated HCl was added (0.5 mL) and the mixture was stirred at room temperature overnight. After two more additions of concentrated HCl (0.5 mL each) and 5 more hours of stirring, the reaction mixture was diluted with water and neutralized with 32% NaOH. It was then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure, A 1.1 mixture of the title product and 4-[3-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl]pyridine-2-carboxamide was obtained. The two products were separated by flash chromatography on silica gel (gradient cyclohexane/AcOEt 2:8 to pure AcOEt), giving 21 mg of the title compound and 15 mg of 4-[3-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl]pyridine-2-carboxamide as white solids. HPLC (254 nm): Rt: 6.26 min; 1H NMR (DMSO-d6) Shift: 10.67 (s, 1H), 8.59 (s, 1H), 8.52 (d, J=5.2 Hz, 1H), 7.80 (s, 1H), 7.62-7.51 (m, 1H), 7.51-7.43 (m, 1H), 7.43-7.31 (m, 3H), 7.31-7.22 (m, 2H), 4.58-4.36 (m, 1H), 3.98 (dd, J=3.0, 11.7 Hz, 2H), 3.58-3.41 (m, 2H), 2.16-2.04 (m, 2H), 2.04-1.84 (m, 2H); HRMS (ESI) calcd for C26H21F3N5O3S [M+H]+ 540.1312. found 540.1332.