Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([O:16][C:17]([F:20])([F:19])[F:18])[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]#[CH:35])=[N:32][CH:33]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]#[C:35][C:2]3[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[C:4]([O:16][C:17]([F:20])([F:19])[F:18])[CH:3]=3)=[N:32][CH:33]=2)=[CH:26][CH:27]=1
Reactant: FC(F)(F)Oc1cc(I)ccc1OCCN1CCCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: FC(F)(F)Oc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-2-trifluoromethoxy-phenoxy)-ethyl]-pyrrolidine (250 mg, 0.62 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (140 mg, 0.65 mmol).
Reaction SMILES: C(N(CC)C(C)C)C.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][N:16]=1.[N:24]1([NH2:33])[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH:26]=[CH:25]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:24]1([NH:33][C:21]([C:18]2[CH:19]=[N:20][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=3)=[N:16][CH:17]=2)=[O:23])[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH:26]=[CH:25]1
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1
Reactant: Nn1ccc2cccnc21
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(Nn1ccc2cccnc21)c1cnc(-c2ccccn2)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
Diethyl-iso-propylamine (1.13 mmol) is added a solution of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (0.75 mmol), pyrrolo[2,3-b]pyridine-1-ylamine (0.75 mmol) and TBTU in anhydrous DMF (7 mL) at rt, and the reaction mixture is stirred at 80° C. overnight. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with water twice, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10% MeOH in DCM to give a crude product. The product is crystallized from EtOAc to afford 2-pyridin-2-yl-pyrimidine-5-carboxylic acid pyrrolo[2,3-b]pyridine-1-ylamide (78 mg, 25%) as a solid. MS: 317 (M+H); 1H NMR (300 MHz, CD3OD): δ 6.56 (m, H) 7.24 (m, H), 7.53 (m, H), 7.61 (m, H), 8.01-8.17 (m, 2H), 8.27 (d, H), 8.69 (m, H), 8.78(m, H), 9.51 (s, 2H).
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[Cl:51])=[C:41]([S:52]([CH3:55])(=[O:54])=[O:53])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[Cl:51])=[C:41]([S:52]([CH3:55])(=[O:53])=[O:54])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CS(=O)(=O)c1cc(Br)ccc1-c1ccccc1Cl
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(-c2ccccc2Cl)c(S(C)(=O)=O)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-2′-chloro-2-(methylsulfonyl)biphenyl (Intermediate 215), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:9]([OH:12])[CH2:10][CH3:11]>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:12][CH2:9][CH2:10][CH3:11])[CH:7]=1
Reactant: CCCO
Reactant: Brc1cncc(Br)c1
Product: CCCOc1cncc(Br)c1
Reaction time: 4 h
Yield: 25 %

Procedure:
n-Propanol and 3,5-dibromopyridine were processed as described in Example 7A except that the heating time was extended to 4 hours. The reaction mixture was quenched onto ice/water, extracted with ethyl ether, and concentrated under reduced pressure. The residue was purified on silica gel (hexanes:ethyl acetate, 8:2) to provide the title compound as a colorless oil (25% yield). MS (DCI/NH3) m/z 216/218 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:42])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][C:40]=2[CH3:41])[CH:30]=1)=O)(C)(C)C.[C:44](O)([C:46]([F:49])([F:48])[F:47])=[O:45]>C(Cl)Cl>[CH3:41][C:40]1[CH:39]=[CH:38][N:37]=[CH:36][C:35]=1[C:31]1[CH:30]=[C:29]([C:27]2[CH2:26][C:25](=[O:42])[NH:24][C:9]3[CH:10]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:12]([O:45][CH2:44][C:46]([F:49])([F:48])[F:47])=[CH:13][C:8]=3[N:7]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccncc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(OCC(F)(F)F)cc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Product: Cc1ccncc1-c1cccc(C2=Nc3cc(OCC(F)(F)F)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from [2-{3-[3-(4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M212) (304 mg, 0.545 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (180 mg, 60%).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH:16]1([O:20][C:21]2[N:26]=[CH:25][C:24]([CH:27]([NH2:29])[CH3:28])=[CH:23][C:22]=2[CH3:30])[CH2:19][CH2:18][CH2:17]1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH:27]([C:24]3[CH:25]=[N:26][C:21]([O:20][CH:16]4[CH2:19][CH2:18][CH2:17]4)=[C:22]([CH3:30])[CH:23]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1OC1CCC1
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OC1CCC1
Yield: 59 %

Procedure:
The title compound is prepared in 59% yield (431 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (574 mg, 2.06 mmol, Step-1 of Intermediate-1) and 1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethanamine hydrochloride (500 mg, 2.06 mmol, Amine-75, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([CH3:15])[C:11]2=O)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1[O:22][CH2:23][CH:24]([CH3:26])[CH3:25])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:13]=[C:12]2[C:8](=[C:7]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:6]=1[O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:9][C:10]([CH3:15])=[CH:11]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(C)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: CC1=Cc2cc(C(C)(C)C)c(OCC(C)C)c(-c3ccccc3)c2C1
Temperature: 5 °C
Reaction time: 7 h
Yield: 99.9 %

Procedure:
To a solution of 34.0 g (97.0 mmol) of 6-tert-butyl-5-isobutoxy-2-methyl-4-phenylindan-1-one in 300 ml of THF cooled to 5° C. 5.00 g (132 mmol) of NaBH4 was added. Further on, 150 ml of methanol was added dropwise to this mixture by vigorous stirring for ca. 7 h at 5° C. The resulting mixture was evaporated to dryness, and the residue was partitioned between 500 ml of dichloromethane and 500 ml of 1 M HCl. The organic layer was separated, the aqueous layer was additionally extracted with 100 ml of dichloromethane. The combined organic extract was evaporated to dryness to give a colorless oil. To a solution of this oil in 500 ml of toluene 1 g of TsOH was added, and this mixture was refluxed with Dean-Stark head for 15 min and then cooled to room temperature using a water bath. The resulting solution was washed by 10% aqueous Na2CO3. The organic layer was separated, the aqueous layer was extracted with 2×100 ml of dichloromethane. The combined organic solution was dried over K2CO3 and then passed through a short pad of silica gel 60 (40-63 um). The silica gel pad was additionally washed by 100 ml of dichloromethane. The combined organic elute was evaporated to dryness. This procedure gave 32.4 g (99%) of 5-tert-butyl-6-isobutoxy-2-methyl-7-phenyl-1H-indene which was further used without an additional purification.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]([NH2:16])([NH2:15])=[N:11][C:12]([NH2:14])=[S:13]>C(O)C>[BrH:1].[NH:11]([C:12]1[S:13][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:14]=1)[C:10]([NH2:16])=[NH:15]
Reactant: NC(=S)N=C(N)N
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: Br
Product: CCOC(=O)c1csc(NC(=N)N)n1
Temperature: 25 °C

Procedure:
13.9 ml of ethyl bromopyruvate are added to a solution of 11.81 g of 2-imino-4-thiobiuret (Aldrich) in 100 ml of ethanol and the reaction mixture is heated under reflux for 3 hours (J. Med. Chem. 34, 914-918 (1991)). Subsequently, the mixture is cooled to room temperature and the reaction product is precipitated by the addition of 550 ml of ethyl acetate and filtered off. There are obtained 14.6 g of yellowish ethyl 2-guanidino-thiazole-4-carboxylate hydrobromide. MS: 214 (M)+.
Reaction SMILES: CS(O[N:6]=[C:7](Cl)[C@H:8]1[CH2:12][O:11][C:10]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[O:9]1)(=O)=O.[S-:19][C:20]#[N:21].[Na+].N1C=CC=CC=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35][C:36]1[CH:37]=[C:38]([O:43][C:44]2[C:45]([CH3:51])=[N:46][N:47]([CH3:50])[C:48]=2[CH3:49])[C:39]([NH2:42])=[N:40][CH:41]=1>O.C(#N)C>[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35][C:36]1[CH:37]=[C:38]([O:43][C:44]2[C:45]([CH3:51])=[N:46][N:47]([CH3:50])[C:48]=2[CH3:49])[C:39]([NH:42][C:20]2[S:19][N:6]=[C:7]([C@H:8]3[CH2:12][O:11][C:10]4([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]4)[O:9]3)[N:21]=2)=[N:40][CH:41]=1
Reactant: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Reactant: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1N
Reactant: N#C[S-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Temperature: 40 °C
Yield: 54.6 %

Procedure:
A flask was charged with (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (2.32 g, 7.79 mmol), sodium thiocyanate (0.557 g, 6.87 mmol), pyridine (1.67 ml, 20.6 mmol), and acetonitrile (101 mL). The reaction was heated to 40° C. for 30 minutes, then 5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-amine (1.5 g, 4.58 mmol) was added and the reaction was heated to 70° C. overnight. Water was added and the reaction was extracted with ethyl acetate and dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified over silica gel (50-100% ethyl acetate in hexanes) to afford (S)-N-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decane-2-yl)-1,2,4-thiadiazol-5-amine (1.38 g, 2.50 mmol, 54.6% yield) as yellow solid.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>O1CCCC1>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(-c2ccccn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#Cc1ccc(-c2ccccn2)cc1
Yield: 89.6 %

Procedure:
A solution of (2) (2.26 g, 8.97 mmol) and tetrabutylammonium fluoride (1 M in tetrahydrofuran, 36 mL, 36 mmol) in tetrahydrofuran was stirred at room temperature under argon for 3 hours. Dichloromethane (100 mL) and water (150 mL) were added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×15 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous magnesium sulfate, filtered and the solvent completely removed. The residue was purified by passing through a silica plug using dichloromethane as eluent to give (3) (1.44 g, 90%).
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][C:27]3[C:36]4[C:31](=[C:32]([CH3:39])[C:33]([O:37][CH3:38])=[CH:34][CH:35]=4)[N:30]=[C:29]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=4)[N:28]=3)[CH2:12]1)[C:8](=[O:47])[NH:7]2)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[F:46][C:42]1[CH:41]=[C:40]([C:29]2[N:28]=[C:27]([O:26][CH:11]3[CH2:10][CH:9]4[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]5[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]4=[O:47])[CH2:23]5)[CH2:12]3)[C:36]3[C:31](=[C:32]([CH3:39])[C:33]([O:37][CH3:38])=[CH:34][CH:35]=3)[N:30]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3nc(-c4cccc(F)c4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3cccc(F)c3)nc2c1C
Temperature: 50 °C
Yield: 82.6 %

Procedure:
The ethyl ester 158 (460 mg, 0.713 mmol) was dissolved in THF:MeOH:H2O (2:1:1, 100 mL) and LiOH (1M) (7.13 mL mg, 7.13 mmol) was added to the solution. The reaction was heated to 50° C. for 16 hrs. THF and MeOH was then removed by rotary evaporation and the remaining solution was acidified with 20 mL 10% citric acid (aq). The water phase was extracted with CHCl3 (3×50 mL) and the organic phase was washed with brine. The organic phase was dried with Na2SO4, filtered and concentrated by rotary evaporation. The product was obtained as a white solid (0.363 g, 82%), LRMS (M+H) 617.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:30][CH:31]([C:33]1[C:34](=[O:47])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)=[N:37][N:38]=1)[CH3:32].[C:48]([CH:51]([CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C:52](O)=[O:53])(=[O:50])[CH3:49]>>[C:48]([CH:51]([CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C:52]([NH:30][CH:31]([C:33]1[C:34](=[O:47])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)=[N:37][N:38]=1)[CH3:32])=[O:53])(=[O:50])[CH3:49]
Reactant: Cc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1
Reactant: CCCCCCC(C(C)=O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCCCCCC(C(C)=O)C(=O)NC(C)c1nnc(Cc2ccc(C)cc2)[nH]c1=O

Procedure:
The amount of 2-acetyloctanoic acid in dichloromethane from Example 19A is reacted analogously to Example 23A with 2.14 g (15.8 mmol) of 1-hydroxy-1H-benzotriazole, 1.90 g (18.8 mmol) of 4-methylmorpholine, 3.03 g (15.8 mmol) of N′-(3-dimethylaminopropyl-N-ethylcarbodiimide hydrochloride and 3.80 mg (15.6 mmol) of 6-(1-aminoethyl)-3-(4-methylbenzyl)-1,2,4-triazin-5(4H)-one (Example 8A) to give 2-acetyl-N-{1-[3-(4-methylbenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}octanamide.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH3:2].[C:25](Cl)(=[O:27])[CH3:26].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[C:25]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[O:12][CH3:13])[N:3]([CH2:1][CH3:2])[C:4]([C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[C:5]2[C:14]#[N:15])(=[O:27])[CH3:26]
Reactant: CCn1c(-c2ccc([N+](=O)[O-])cc2)c(C#N)c2ccc(OC)cc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCn1c(-c2ccc([N+](=O)[O-])cc2)c(C#N)c2cc(C(C)=O)c(OC)cc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 30.3 %

Procedure:
1-Ethyl-6-methoxy-2-(4-nitrophenyl)-1H-indole-3-carbonitrile (100 mg, 0.3 mmol), prepared by the method of example 1Gc was suspended in 1,2-dichloroethane (500 mL) at 0° C. Acetyl chloride (50 μL, 0.69 mmol) was added, followed by AlCl3 (55 mg, 0.4 mmol) in one portion. This was stirred at 0° C. for 1 hour, at room temperature for 4 hours, and at 45° C. overnight. The reaction mixture was then partitioned between CH2Cl2 and H2O. The organic layer was dried and concentrated. Purification by silica gel chromatography (195:5 CH2Cl2/EtOAc) yielded 5-acetyl-1-ethyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile (33 mg, 29%) as an orange solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:21](=[O:22])[CH2:20][S:19][C:18]3=[O:23])(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:24](=O)[CH2:25][CH2:26][CH3:27].N1CCCCC1>C(O)C>[CH:24](=[C:20]1[S:19][C:18](=[O:23])[N:17]([CH2:16][CH2:15][CH2:14][CH2:13][S:10]([C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)(=[O:12])=[O:11])[C:21]1=[O:22])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCCCS(=O)(=O)c1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCCS(=O)(=O)c2cccc3nccn23)C1=O

Procedure:
To a solution of 0.22 g (0.62 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylsulfonyl)butyl]thiazolidine-2,4-dione and 0.10 ml (1.1 mmol) of n-butyraldehyde in 5 ml of ethanol, 0.01 ml (0.1 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4) to yield 0.269 g (quant., yellow oily substance) of the desired product.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][C@@H:6]([OH:8])[CH2:5][C@@H:4]1[C:9]([OH:11])=[O:10])[CH3:2].[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.[Si](O[C@H]1C[C@H](C(O)=O)[C@H](CC)C1)(C(C)(C)C)(C)C>[Si:16]([O:8][CH:6]1[CH2:5][CH:4]([C:9]([OH:11])=[O:10])[CH:3]([CH2:1][CH3:2])[CH2:7]1)([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC[C@@H]1C[C@@H](O)C[C@@H]1C(=O)O
Agent: CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCC1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a scalemic mixture enriched in (1S,2R,4R)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (2.56 g, 16.21 mmol) in DMF (10.81 mL) was added TBDMSCl (2.93 g, 19.45 mmol) and imidazole (2.76 g, 40.5 mmol). The reaction mixture was stirred at ambient temperature for about 2 days then extracted with pentane (3×25 mL). The combined pentane layers were washed with water (25 mL) and brine (25 mL), dried over anhydrous MgSO4, filtered and concd under reduced pressure. The residue was purified using silica gel chromatography eluting with 20-100% EtOAc in heptane give a scalemic mixture enriched in (1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylic acid (1.13 g, 26%): LC/MS (Table 1, Method b) Rt=3.03 min; MS m/z: 273 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[N+:21]([C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=2)=[O:32])[C:3]1=[O:20]
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2cccc([N+](=O)[O-])c2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-nitrophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 288°-289° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[C:54]1([N:60]=[C:61]=[O:62])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:61]([NH:60][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:62])[CH2:48]1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)Nc2ccccc2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 99 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and phenyl isocyanate as the starting materials in 99% yield. LCMS for C30H30ClN8O2 (M+H)+: m/z=569.1.