Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH:9]([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH:20]([C:23]1[N:24]=[C:25]([CH2:28][CH2:29][C:30]2[CH:42]=[CH:41][N:33]3[C:34](=[O:40])[C:35]([CH:38]=O)=[CH:36][N:37]=[C:32]3[CH:31]=2)[S:26][CH:27]=1)([CH3:22])[CH3:21].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[CH:20]([C:23]1[N:24]=[C:25]([CH2:28][CH2:29][C:30]2[CH:42]=[CH:41][N:33]3[C:34](=[O:40])[C:35](/[CH:38]=[C:9](\[CH3:17])/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:36][N:37]=[C:32]3[CH:31]=2)[S:26][CH:27]=1)([CH3:22])[CH3:21]
Reactant: CCOP(=O)(OCC)C(C)C(=O)OC(C)(C)C
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(C=O)cnc3c2)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C/C(=C\c1cnc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
tert-Butyl 2-(diethylphosphono)propionate (70 mg) was dissolved in tetrahydrofuran(5 ml), added with sodium hydride (60% in oil, 40 mg), and stirred for 10 minutes. The reaction mixture was added with 8-(2-(4-isopropyl-1,3-thiazol-2-yl)-ethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde (56 mg), stirred for 10 minutes and added with acetic acid (0.2 ml), and then distributed between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound (70 mg) as yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][CH2:30]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:13])[F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:28][C@H:29]4[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:31][CH2:30]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[C@@H:4]([CH2:59][CH:60]([CH3:62])[CH3:61])[NH:5][C:6](=[O:58])[C@H:7]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:46][CH:45]=1)[NH:8][C:9](=[O:42])[C@H:10]([CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH:11][C:12](=[O:32])[C@H:13]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:14][C:15]([O:17]C(C)(C)C)=O.FC(F)(F)C(O)=O.[CH:71]1(C(O)=O)[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:63])[C@@H:4]([CH2:59][CH:60]([CH3:62])[CH3:61])[NH:5][C:6](=[O:58])[C@H:7]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:46][CH:45]=1)[NH:8][C:9](=[O:42])[C@H:10]([CH2:33][O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH:11][C:12](=[O:32])[C@H:13]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:14][C:15]([CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1)=[O:17]
Reactant: O=C(O)C1CCCCC1
Reactant: COC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C1CCCCC1

Procedure:
Nα-t-Butoxycarbonyl-L-tryptophyl-O-benzyl-L-seryl-O-benzyl-L-tyrosyl-D-leucine methyl ester (Example 17), 1 g., 1.16 mmol, is reacted according to the appropriate part of Example 1 with 20 ml. of trifluoroacetic acid, neutralized with triethylamine and coupled with 150 mg., 1.17 mmol, of cyclohexane carboxylic acid using 180 mg., 1.17 mmol, of 1-hydroxybenzotriazole and 240 mg., 1.17 mmol, of dicyclohexylcarbodiimide. The solution is evaporated and the residue triturated with ether. The product is precipitated from isopropanol on cooling as a cream solid; 1 g.; m.p. 158°-160° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][CH:15]([S:18]([OH:21])(=O)=[O:19])[CH2:14][CH2:13]1.P(Cl)(Cl)(Cl)(Cl)[Cl:23]>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][CH:15]([S:18]([Cl:23])(=[O:21])=[O:19])[CH2:14][CH2:13]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(S(=O)(=O)O)CC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1C1CCC(S(=O)(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
A mixture of 4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-sulfonic acid (6.8 g, 22 mmol) and PCl5 (5 g, 24 mmol) was stirred at room temperature for 30 min. And then the mixture was heated at 100° C. and stirred for 2 h. After cooling to room temperature, the mixture was washed with EtOAc (150 mL×3). The combined extracts were concentrated in vacuo to give crude 4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-sulfonyl chloride (5 g, 68%) as a whit solid, which was used in the next step directly.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([OH:6])=[O:5].S(Cl)([Cl:9])=O.[CH2:11](O)[CH2:12][CH2:13][CH3:14]>>[Cl-:9].[NH2:2][CH2:3][C:4]([O:6][CH2:11][CH2:12][CH2:13][CH3:14])=[O:5]
Reactant: CCCCO
Reactant: NCC(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CCCCOC(=O)CN
Product: [Cl-]
Temperature: 70 °C

Procedure:
To a suspension of glycine hydrochloride (10 g, 89.6 mmol) in 250 mL butanol under nitrogen was added thionyl chloride (45.7 mL, 627 mmol) dropwise. After the addition was complete, the solution was heated at 70° C. overnight. The volatile components were removed on the roto-evaporator and the residue was suspended and evaporated from toluene three times. The resulting crude gum was dissolved in an equal weight of toluene for easy transfer and was used as is in the next reaction.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[CH3:2].[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.CCOCC.O>CN(C=O)C>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:14]2[C:15]3[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)=[CH:23][CH:22]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCN(CC)CCCCOc1ccc2[nH]ccc2c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCN(CC)CCCCOc1ccc2c(ccn2Cc2ccc(Br)cc2)c1
Yield: 53.6 %

Procedure:
130 mg (0.5 mmol) Diethyl-[4-(1H-indol-5-yloxy)-butyl]-amine in 1 ml DMF were treated with 67 mg (0.6 mmol) potassium tert. butylate and 150 mg (0.6 mmol) 4-bromobenzylbromide at 45° C. for 1 h. Ether and water were added and the organic phase was washed with water and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2: MeOH 9:1 yielded 115 mg (53%) {4-[1-(4-Bromo-benzyl)-1H-indol-5-yloxy]-butyl}-diethyl-amine as colorless oil, MS: 429 (MH+, 1Br).
Reaction SMILES: [CH2:1]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CS(O)(=O)=O.O.[CH2:32]([C:38]1([CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[C:50]2[CH:49]=[C:48]([C:51]3(O)[C:63]4[CH:62]=[C:61]([Br:64])[CH:60]=[CH:59][C:58]=4[C:57]4[C:52]3=[CH:53][C:54]([Br:65])=[CH:55][CH:56]=4)[CH:47]=[CH:46][C:45]=2[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>ClCCl>[CH2:20]([C:7]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:19]2[CH:18]=[C:17]([C:51]3([C:48]4[CH:47]=[CH:46][C:45]5[C:44]6[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=6)[C:38]([CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:50]=5[CH:49]=4)[C:63]4[CH:62]=[C:61]([Br:64])[CH:60]=[CH:59][C:58]=4[C:57]4[C:52]3=[CH:53][C:54]([Br:65])=[CH:55][CH:56]=4)[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2ccccc21
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2ccc(C3(O)c4cc(Br)ccc4-c4ccc(Br)cc43)cc21
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: O
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2ccc(C3(c4ccc5c(c4)C(CCCCCC)(CCCCCC)c4ccccc4-5)c4cc(Br)ccc4-c4ccc(Br)cc43)cc21

Procedure:
In a 2 L round-bottom flask, 50 g of the compound (1) and 200 g of 9,9-dihexylfluorene were dissolved in 1000 ml of dichloromethane, and then the temperature was decreased to 0° C. The reaction solution was slowly added with a s olution of 10 ml of methane sulfonic acid dissolved in 100 ml of dichloromethane with stirring, followed by further stirring for 2 hours. The resulting reaction solution was poured into water, after which an extraction was performed using diethyl ether. The solvent was evaporated using a rotary evaporator. A column chromatography separation resulted in 60 g (58%) of (9,9-di(9,9-dihexylfluoren-2-yl)-2,7-dibromofluorene) (2).
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[F:39][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Yield: 100 %

Procedure:
Reaction of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate from the previous step with an excess of TFA (10 mL) in CH2Cl2 (50 mL) at room temperature for 2 hrs, followed by treatment with aq. NH3 gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole in 100% yield: mp (EtOH) 228-231° C.: 1H NMR (CDCl3) δ 7.90 (d, J=7.9 Hz, 1H), 7.50 (t, JHF=53.5 Hz, 1H), 7.34 (t, J=8.3 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 4.05 (s, 3H), 3.87 (m, 8H), 3.78 (m, 4H), 2.95 (m, 4H); Anal. Calcd. for C20H24F2N8O2: C, 53.8; H, 5.4; N, 25.1. Found: C, 53.8; H, 5.6; N, 25.3%.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.C>O1CCOCC1.[OH-].[Na+]>[F:17][C:14]1[CH:13]=[CH:12][C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cn(-c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Crude 1-(4-fluoro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester (175 mmol) was dissolved in 450 mL dioxane and 450 mL 2N sodium hydroxide solution. The reaction mixture was refluxed for 2 h. Charcoal (1 g, Norit SA II) was added and reflux was continued for another 20 min. The mixture was filtered hot and washed with 50 mL 2N sodium hydroxide solution. The filtrate was treated with 550 mL 2N HCl and stirred at room temperature overnight. The solid material was filtered off and dried at 50° C. and 15 mbar. The desired compound was obtained as an off-white solid (28 g, 78%), MS: m/e=205.1 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[CH2:9][NH:8]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C1C=CC=CC=1>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:8]2[CH2:9][C:10](=[O:14])[NH:11][C:12](=[O:13])[N:7]2[CH2:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C1CNN(Cc2ccc(Cl)cc2)C(=O)N1
Solvent: c1ccccc1
Product: O=C1CN(C(=O)c2ccc(Cl)cc2)N(Cc2ccc(Cl)cc2)C(=O)N1
Yield: 60 %

Procedure:
Into a 100 ml round bottomed flask equipped with a reflux condenser sealed with a calcium chloride tube, were placed 100 ml of dry benzene, 1 g of 2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5-dione and 2 ml of p-chlorobenzoylchloride. The mixture was refluxed for 18 hours, the solution obtained was then cooled and the precipitated crystals were filtered off by suction to yield 1 g (60%) of 1-(4'-chlorobenzoyl)-2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5-dione; m.p. 205°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)[CH:5]=[N:6][C:7]=1[Cl:8].[CH2:23]([O:25][C:26]([Sn](CCCC)(CCCC)CCCC)=[CH2:27])[CH3:24].[Sn]>C1(C)C=CC=CC=1.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>[CH2:26]([O:25][C:23]([C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][NH:12]2)[CH:5]=[N:6][C:7]=1[Cl:8])=[CH2:24])[CH3:27]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Sn]
Solvent: Cc1ccccc1
Product: C=C(OCC)c1cc(OC[C@@H]2CCCN2)cnc1Cl
Temperature: 25 °C

Procedure:
To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine (500 mg, 1.28 mmol) in toluene (10.0 mL) was added (1-ethoxyvinyl)tributyltin (489 mL, 1.41 mmol) and tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.-45 mmol). After being refluxed overnight, the resulting mixture was cooled to room temperature. Solvent was removed and the residue was chromatographed on a silica gel column, eluting with hexane/EtOAc 2:1 and 1:1 to afford an oil (568 mg, >100%; some tin reagent contamination). MS (CI/NH3) m/z 383 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.25-1.45 (m, 3H), 1.47 (s, 9H), 1.55-1.71 (m, 1H), 1.98-2.07 (m, 3H), 3.32-3.45 (m, 1H), 3.87-3.96 (m, 2H), 4.05-4.21 (m, 3H), 4.43-4.47 (m, 2H), 7.26-7.34 (m, 1H), 8.03-8.06 (m, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([C@:6]2([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=4)[CH2:23][CH2:22]3)=[O:20])[CH2:10][CH2:9][C@@H:8]([NH:11]C(=O)OC(C)(C)C)[CH2:7]2)[CH2:2]1.[ClH:37]>CCOCC>[ClH:37].[ClH:37].[O:1]1[CH2:5][CH2:4][C@H:3]([C@:6]2([C:19]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[CH:29][N:28]=4)[CH2:25][CH2:26]3)=[O:20])[CH2:10][CH2:9][C@@H:8]([NH2:11])[CH2:7]2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)([C@H]2CCOC2)C1
Agent: Cl
Solvent: CCOCC
Product: N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)([C@H]2CCOC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl [(1R,3S)-3- [(3R)-tetrahydrofuran-3-yl]-3-(4- [4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]carbamate (260 mg, 0.51 mmol) was dissolved in a 2 M solution of hydrogen chloride in ether (8 mL). After being stirred at room temperature overnight, the reaction mixture was concentrated under vacuum to provide the desired product (290 mg) as a light yellow solid. MS calculated for C20H27F3N4O2: (M+H) 413.2; found 413.0.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[NH:8][C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O.CN(C=O)C>O1CCOCC1>[Cl:16][C:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:10]=2[S:9](=[O:12])(=[O:11])[N:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1NS(=O)(=O)c2c(F)cccc21
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=S1(=O)N=C(Cl)c2cccc(F)c21

Procedure:
3.02 g of 7-fluoro-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (EP291851 A2 19881123), 1.64 ml of thionyl chloride and a catalytic amount of DMF in 13 ml of dioxane are heated under reflux for 45 hours. The mixture is concentrated and the residue is crystallized in toluene. 2.50 g of a crude solid is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH:6]=[CH:5]2
Reactant: OC1CCOc2ccc(F)cc21
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc2c(c1)C=CCO2
Yield: 58.3 %

Procedure:
6-Fluorochroman-4-ol (8 g, 48 mmol) and toluene-4-sulphonic acidn (1 g) were dissolved in toluene and refluxed over-night with subsequent water removal. The mixture was then cooled and washed with NaHCO3 (aq) and purified by chromatography (silica gel, n-hexane) to give 4.2 g (52%) of pure 6-fluoro-2H-chromene. 29c) +/−cis-6-Fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylic acid ethyl ester
Reaction SMILES: C([Mg]Br)C.[CH3:5][C:6]([CH3:12])([CH3:11])[C:7]#[C:8][C:9]#[CH:10].[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].O>CCOCC>[CH3:5][C:6]([CH3:12])([CH3:11])[C:7]#[C:8][C:9]#[C:10][Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C#CC#CC(C)(C)C
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: O
Product: CCCC[Sn](C#CC#CC(C)(C)C)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 16 h
Yield: 39.7 %

Procedure:
(5,5-dimethyl-1,3-hexadiynyl)tri-n-butylstannane was synthesized as follows a solution containing ethylmagnesium bromide (19.3 millimoles) and 5,5-dimethyl-1,3hexadiyne (19.3 millimoles) in 50 milliliters of ether was refluxed for 5 hours under nitrogen, then cooled to -78° C. To this solution, 18.6 millimoles of tri-n-butyltin chloride in 10 milliliters of ether was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. Water was added to form a two-phase mixture, the phases were separated, and the aqueous phase was washed with ether. The ether wash was combined with the organic phase from the initial phase separation, and evaporated under reduced pressure to yield a crude oil. Distillation in vacuo produced 2.92 grams of pure (5,5-dimethyl-1,3-hexadiynyl)tri-n-butylstannane.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.[CH3:10][O:11][CH2:12][C:13](Cl)=[O:14].C([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25](OC(F)(F)F)[CH:26]=2)[N:21]([CH2:33][C:34]([OH:36])=[O:35])[CH:20]=1)(=O)C>>[CH3:10][O:11][CH2:12][C:13]([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:33][C:34]([OH:36])=[O:35])[CH:20]=1)=[O:14]
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Reactant: COCC(=O)Cl
Agent: c1ccc2[nH]ccc2c1
Product: COCC(=O)c1cn(CC(=O)O)c2ccccc12

Procedure:
was prepared from 1H-indole in a similar manner as described in Scheme A13 (in step A, 2-methoxyacetyl chloride was used instead of acetyl chloride) for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. Brown solid. MS: 248.0 [M+H]+; tR (HPLC conditions c): 3.42 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[CH3:17][S:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>C(O)C>[CH3:17][S:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:23]=[CH:24][CH:25]=1
Reactant: CSc1cccc(N)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: CSc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Reaction time: 2 h
Yield: 67 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 3.18 ml (25.8 mmol) 3-methylsulfanylaniline was heated to reflux under N2. At 2 hours, removed heat and made basic with saturated sodium bicarbonate. Stripped solvents and air dried. Washed residue with hexane, collected solids and washed with water. Dissolved in ethyl acetate, stirred with Darco, stripped solvent and dried in vacuo, giving 4.848 g of yellow solid: mass spectrum (electrospray m/e): M+H=337.1.
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:11]([NH2:15])(=[S:14])[CH2:12][CH3:13].O>C(O)C>[CH2:12]([C:11]1[S:14][C:8]([CH3:10])=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:15]=1)[CH3:13]
Reactant: CCC(N)=S
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1nc(CC)sc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.33 ml ethyl 2-chloroacetoacetate and 1.5 g thiopropionamide were dissolved in 30 ml ethanol, followed by stirring at room temperature for 16 hours. The reaction solution was ice-cooled and water was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=14:1), to give 0.8 g of ethyl 2-ethyl-5-methyl-1,3-thiazole-4-carboxylate.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][C:7]([C:10]1[CH:15]=[C:14]([CH:16]([NH:23][OH:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[C:12]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:11]=1[OH:29])([CH3:9])[CH3:8].[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>O.O1CCOCC1>[CH3:26][C:25]([C:12]1[CH:13]=[C:14]([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:23]([OH:24])[C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:15]=[C:10]([C:7]([CH3:6])([CH3:8])[CH3:9])[C:11]=1[OH:29])([CH3:28])[CH3:27]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)c1cc(C(NO)c2ccccc2)cc(C(C)(C)C)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C(=O)N(O)C(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 0.82 g (0.01 mole) of sodium acetate in 7 mL H2O is added to a solution of 1.08 g (0. 0033 mole) of 2,6-bis (1,1-dimethylethyl)-4-[(hydroxyamino)phenylmethyl]phenol in 30 mL dioxane. Isobutyryl chloride (0.51 g, 0. 00477 mole) is added dropwise and the mixture is stirred at room temperature for 17 hours. Water (25 mL) is added to the mixture and the solid material is filtered off and washed with water. After drying it is recrystallized from Et2O-n-hexane to give off-white crystals, 0.477 g (36%), m.p. 179°-180° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([CH3:17])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:9]1[C:25]([N:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:33]OS([O-])=O.[K+]>CO.O>[CH2:1]([N:8]1[C:12]([C:13]([F:15])([F:16])[F:14])=[C:11]([CH3:17])[C:10]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[C:9]1[C:25]([N:27]1[CH2:28][CH2:29][S:30](=[O:33])[CH2:31][CH2:32]1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N2CCSCC2)n(Cc2ccccc2)c1C(F)(F)F
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N2CCS(=O)CC2)n(Cc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of (1-benzyl-3-(4-chlorophenyl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(thiomorpholino)methanone [for synthesis see SC-26] (131 mg, 0.28 mmol) in MeOH (4 mL) and H2O (1 mL) was added oxone (85 mg, 0.138 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H2O and extracted with DCM (60 mL). The organic layer was washed with brine, dried (Na2SO4) and purified by flash column chromatography (silica, heptane/EtOAc, 1:1→0:1) to give SC-19 (48 mg, 35%) as a white foam.