Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH:15][C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17])[S:13][CH:14]=1)[C:5]([O:7]CC)=[O:6].O>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH:15][C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:21])[Cl:22])=[O:17])[S:13][CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Solvent: O
Solvent: CCO
Product: CON=C(C(=O)O)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.1 g. of ethyl α-methoxyimino-[2-(β,β,β-trichloroethoxycarbonylamino)thiazol-4-yl]acetate in 50 ml. of ethanol is added a solution of 11.2 g. of KCH in a mixture of 30 ml. of water and 150 ml. of ethanol. The whole mixture is stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The residue is extracted with ethyl acetate. The water layer is made acidic with 10% aq. HCl and the separated solid is collected. Recrystallization of the solid from aq. methanol gives α-methoxyimino-[2-(β,β,β-trichloroethoxycarbonylamino)-thiazol-4-yl]acetic acid. 4.1 g. Melting point: 162°-163° C.
Reaction SMILES: [N+:1]([C:4]1[CH:39]=[CH:38][C:7]([CH2:8][N:9]2[C:15](=[O:16])[C@H:14]3[CH2:17][CH2:18][CH2:19][C@H:13]3[N:12]([C:20](=[O:33])[CH2:21][N:22]3[C:26](=[O:27])[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=[O:32])[C:11]3[CH:34]=[CH:35][CH:36]=[CH:37][C:10]2=3)=[CH:6][CH:5]=1)([O-])=O>CO.[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:15](=[O:16])[C@H:14]3[CH2:17][CH2:18][CH2:19][C@H:13]3[N:12]([C:20](=[O:33])[CH2:21][N:22]3[C:23](=[O:32])[C:24]4=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]4[C:26]3=[O:27])[C:11]3[CH:34]=[CH:35][CH:36]=[CH:37][C:10]2=3)=[CH:38][CH:39]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccc([N+](=O)[O-])cc2)C(=O)[C@H]2CCC[C@H]21
Agent: O=[Pt]
Solvent: CO
Product: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.3 %

Procedure:
A suspension of (3aR*,10aS*)-9-(4-nitrobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (110 mg, 0.21 mmol) and platinum oxide (20 mg) in methanol (20 mL) was stirred for 12 hours at room temperature under hydrogen atmosphere. The reaction mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure, which was crystallized from diethyl ether to give 72 mg (yield 81%) of the object compound, m.p.286°-289° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].[S:13](Cl)(=[O:16])(=[O:15])[NH2:14]>>[C:4]([C:3]1[CH:6]=[C:7]([CH:10]([CH3:12])[CH3:11])[CH:8]=[CH:9][C:2]=1[NH:1][S:13]([NH2:14])(=[O:16])=[O:15])#[N:5]
Reactant: CC(C)c1ccc(N)c(C#N)c1
Reactant: NS(=O)(=O)Cl
Product: CC(C)c1ccc(NS(N)(=O)=O)c(C#N)c1

Procedure:
Prepared as in Example 77a from 2-Amino-5-isopropylbenzonitrile (Example 87b) and sulfamoyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=O)[C@H:10]([CH2:15][N:16]([CH:33]2[CH2:35][CH2:34]2)[C:17](=[O:32])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:36]1([NH2:39])[CH2:38][CH2:37]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:15][N:16]([CH:33]2[CH2:35][CH2:34]2)[C:17](=[O:32])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=2)[C@H:11]([CH2:13][NH:39][CH:36]2[CH2:38][CH2:37]2)[CH2:12]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: NC1CC1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C2CC2)ccc1OC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C2CC2)ccc1OC

Procedure:
In a similar manner as described in Example 149 for the reaction step D, the following starting material is prepared from (3R,4S)-3-({cyclopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.79 g, 3.65 mmol) (prepared according to example 9 using cyclopropyl amine instead of isopropyl amine under F), cyclopropyl amine (0.287 mL, 4.01 mmol) and NaBHOAc3 (1.14 g, 5.11 mmol) to give the title compound which is used in the next steps without further purification. TLC, Rf (CH2Cl2/AcOEt 9:1)=0.35. MS (LC-MS): 532.0 [M+H]+.
Reaction SMILES: FC(F)(F)C([O-])=O.C1(CC([NH:17][C@@H:18]2[C:39](=[O:40])[N:20]3[C:21]([C:36]([OH:38])=[O:37])=[C:22](/[CH:25]=[CH:26]/[CH2:27][N+:28]([CH2:32][C:33](=[O:35])[NH2:34])([CH2:30][CH3:31])[CH3:29])[CH2:23][S:24][C@H:19]23)=O)C=CC=CC=1.CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O>>[NH2:17][C@@H:18]1[C:39](=[O:40])[N:20]2[C:21]([C:36]([O-:38])=[O:37])=[C:22](/[CH:25]=[CH:26]/[CH2:27][N+:28]([CH2:32][C:33](=[O:35])[NH2:34])([CH2:30][CH3:31])[CH3:29])[CH2:23][S:24][C@H:19]12
Reactant: CC[N+](C)(C/C=C/C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1)CC(N)=O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: O=C([O-])C(F)(F)F
Product: CC[N+](C)(C/C=C/C1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1)CC(N)=O
Yield: 23.8 %

Procedure:
In a similar manner as in Example 6 except for the use of paratoluenesulfonic acid monohydrate in place of perchloric acid, the compound (5.9 g) of Example 12 was hydrolyzed using "Carrier-Fixed Penicillin G Amidase" (5.9 g) to obtain the target product (0.85 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](Cl)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[Na+].[CH3:35][S:36]([NH-:39])(=[O:38])=[O:37]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[C:10]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])[N:11]=[C:2]([Cl:1])[CH:3]=1
Reactant: CS([NH-])(=O)=O
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)nc(NS(C)(=O)=O)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 49.5 %

Procedure:
Add methyl 2,6-dichloro-isonicotinate (2.06 g, 10.0 mmol), toluene (10 mL), tris(dibenzylideneacetone)dipalladium(0) (0.458 g, 0.50 mmol), 2-(di-tert-butylphosphino)biphenyl (0.298 g, 1.00 mmol), and methanesulfonamide sodium salt (1.17 g, 10.0 mmol) to a sealed flask flushed with nitrogen. Heat and stir the sealed flask at 100° C. for 18 h. Cool the mixture to room temperature and filter through a pad of filtering agent, and wash the solid with dichloromethane. Concentrate and purify (silica gel chromatography, eluting with 20:80 to 30:70 ethyl acetate:hexanes) to give the title compound (1.31 g, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:9])=O)=[O:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:42][C@@H:43]([CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C@@H:44]([OH:62])[CH2:45][C@@H:46]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[CH2:63]([C@H:43]([NH:42][C:7]([C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[C@@H:44]([OH:62])[CH2:45][C@@H:46]([NH:54][C:55]([O:56][C:57]([CH3:58])([CH3:59])[CH3:60])=[O:61])[CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
A solution of the product from Example 1F (7.0 g, 37.0 mmol), EDAC (8.5 g, 44.3 mmol), HOBT (6.0 g, 44.4 mmol), and NMM (8.0 mL, 72.8 mmol) in DMF (30 mL) was stirred at 25° C. for 1 hour, treated with a solution of the product from Example 6A (14.15 g, 36.8 mmol) in DMF (30 mL), stirred at 25° C. for 16 hours, concentrated, and partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with saturated NaHCO3 and brine, and concentrated. The solution of the residue in hot methanol (20 mL) and water (10 mL) was allowed to cool and stand for 16 hours. The solids were collected by filtration and rinsed several times with hexanes, followed by drying under vacuum to give the title compound (16.97 g, 77% yield).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:19]([OH:30])[CH2:20][CH:21]2[CH2:29][CH2:28][C:23]3([O:27][CH2:26][CH2:25][O:24]3)[CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](=[O:30])[CH2:20][CH:21]2[CH2:29][CH2:28][C:23]3([O:27][CH2:26][CH2:25][O:24]3)[CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCC3(C2)OCCO3)cc2cccnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(CC1CCC2(C1)OCCO2)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(1,4-dioxa-spiro[4.4]non-7-yl)-ethanol (2.5 g, 5.84 mmol) in dichloromethane (150 mL) was added Dess-Martin periodinane (6.2 g, 14.6 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 h and then quenched with a saturated aqueous sodium bicarbonate solution (100 mL). The mixture was extracted with dichloromethane (50 mL), washed with a saturated aqueous sodium bicarbonate solution (3×100 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 50% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(1,4-dioxa-spiro[4.4]non-7-yl)-ethanone (2.45 g, 98%) as a light yellow solid: LC/MS m/e calcd for C22H22N2O5S [M+H]+ 427.50, observed 427.5.
Reaction SMILES: C[N:2]1C=C2C(C=CC=C2)=N1.C([Li])CCC.S(=O)(O)O.NOS(O)(=O)=O.[OH-].[Na+].[CH3:28][N:29]1[C:37]([S:38]([O-:40])=[O:39])=[C:36]2[C:31]([CH:32]=[CH:33][CH:34]=[CH:35]2)=[N:30]1.[Li+]>C(OCC)C.O.CCCCCC>[CH3:28][N:29]1[C:37]([S:38]([NH2:2])(=[O:40])=[O:39])=[C:36]2[C:31]([CH:32]=[CH:33][CH:34]=[CH:35]2)=[N:30]1
Reactant: Cn1nc2ccccc2c1S(=O)[O-]
Reactant: Cn1cc2ccccc2n1
Agent: NOS(=O)(=O)O
Agent: O=S(O)O
Agent: [Li+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: Cn1nc2ccccc2c1S(N)(=O)=O
Temperature: -30 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution containing 9.5 g (72 mmol) of 2-methyl-2H-indazole in 200 ml of ethyl ether, was cooled to -30° C., and 61.4 g (144 mmol) of n-butyl lithium (a 15% hexane solution) was dropwise added thereto. The mixture was stirred for one hour at the same temperature, and then an excess amount of sulfurous acid gas was blown thereinto for 3 hours at a temperature of not higher than -20° C. After completion of the reaction, the mixture was returned to room temperature, stirred for 12 hours and then diluted with ethyl ether. The product was subjected to filtration. The crystals were dried to obtain crude lithium 2-methyl-2H-indazole-3-sulfinate. This product was used for the subsequent reaction without purification. 48.8 g (430 mmol) of hydroxylamine-O-sulfonic acid was gradually added to a solution containing 17.2 g (430 mmol) of sodium hydroxide in water (300 ml) under cooling with ice (not higher than 10° C.). This solution was added all at once to a solution containing the crude lithium 2-methyl-2H-indazole-3-sulfinate previously prepared in water (100 ml), and then the mixture was stirred for 12 hours at room temperature. Formed crystals were collected by filtration to obtain 8.8 g (yield: 58%) of 2-methyl-2H-indazole-3-sulfonamide (slightly yellow granular crystals). Melting point: 181°-183° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[C:32]2[C:27](=[C:28]([Cl:33])[CH:29]=[CH:30][CH:31]=2)[N:26]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][OH:44])=[CH:37][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54].Cl>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[C:32]2[C:27](=[C:28]([Cl:33])[CH:29]=[CH:30][CH:31]=2)[N:26]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][S:53]([CH3:52])(=[O:55])=[O:54])=[CH:37][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cn(Cc3ccc(OCCO)cc3)c3c(Cl)cccc23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](c2cn(Cc3ccc(OCCOS(C)(=O)=O)cc3)c3c(Cl)cccc23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-7-chloro-1-[4-(2-hydroxyethoxy)benzyl]-1H-indole (0.23 g) and triethylamine (0.076 mL) in dichloromethane (4 mL) was added methanesulfonyl chloride (0.034 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-7-chloro-1-{4-[2-(methanesulfonyloxy)ethoxy]-benzyl}-1H-indole (0.25 g).
Reaction SMILES: [C:1]1(OP([O-])(OC2C=CC=CC=2)=O)C=CC=C[CH:2]=1.C([N+](CCCC)(CCCC)CCCC)CCC.[C:35]([O-:43])(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([NH+](CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.S(Cl)(Cl)(=O)=O.C(O)C>N1C=CC=CC=1>[C:35]([O:43][CH2:1][CH3:2])(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C([O-])c1ccccc1
Reactant: O=P([O-])(Oc1ccccc1)Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[NH+](CC)CC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1ccccc1
Yield: 16 %

Procedure:
The applicant also examined whether other acids can be converted to acid chlorides by this reagent. Reaction of PPh3 /SO2Cl2 with tetra-n-butyl ammonium diphenyl phosphate followed by quenching with ethanol in pyridine led to the phosphate triester in 63% isolated yield, indicating that this reaction may also be useful for the activation of phosphate diesters under very mild conditions. The same reaction does not appear to be preferred for the synthesis of acid chlorides from carboxylates. For example, treatment of triethylammonium benzoate with PPh3 /sulfuryl chloride, followed by the addition of ethanol in pyridine gave ethyl benzoate in only 16% yield. These results indicate that less nucleophilic salts such as sulfate monoesters, or sulfamates are likely to be better substrates for this type of activation than more nucleophilic ones.
Reaction SMILES: CON(C)[C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1.[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:15]1([C:4](=[O:13])[CH2:5][C:6]2[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)Cc1cccc(C)c1
Solvent: C1CCOC1
Product: Cc1cccc(CC(=O)c2ccccc2)c1
Reaction time: 3 h
Yield: 84.1 %

Procedure:
Under N2, to a mixture of N-methoxy-N-methyl-2-m-tolylacetamide (500 mg, 2.6 mmol) in anhydrous THF was added phenylmagnesium bromide (6.5 mL, 6.5 mmol) at −78° C., and the mixture was stirred for 3 hours. When TLC indicated that the starting material was consumed, the reaction mixture was diluted with EtOAc, washed with water and brine, concentrated, and purified by column chromatography (PE:EtOAc=30:1) to give Intermediate 4 (460 mg, yield 84.6%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([NH2:9])[N:5]=[C:4]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:11]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[C:36](N1C=CN=C1)(N1C=CN=C1)=[O:37]>CN(C)C=O>[NH2:9][C:6]1[C:7]2[O:8][C:36](=[O:37])[NH:1][C:2]=2[N:3]=[C:4]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:11]=2)[N:5]=1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
159 mg (0.453 mmol) of the compound prepared in example 58A in dimethylformamide (10 ml) were admixed with 94 μl (0.543 mmol) of N,N-diisopropylethylamine and 88 mg (0.543 mmol) of carbonyldiimidazole, and the mixture was stirred at RT overnight. The mixture was filtered, the filtrate was concentrated and the residue was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 90 mg of the title compound were obtained (52% of theory).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[C:11]=2[CH3:14])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].[CH:18]([C:20]([CH2:22][CH3:23])=[O:21])=[CH2:19].N12CCCN=C1CCCCC2>O1CCCC1.CCOC(C)=O>[CH2:1]([C:5]1([CH2:19][CH2:18][C:20](=[O:21])[CH2:22][CH3:23])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[C:11]=2[CH3:14])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(=O)CC
Reactant: CCCCC1Cc2c(ccc(OC)c2C)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCC1(CCC(=O)CC)Cc2c(ccc(OC)c2C)C1=O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A solution of 2-butyl-5-methoxy-4-methyl-1-indanone (100 mg, 0.43 mmol) in tetrahydrofuran (0.43 mL) was treated with ethyl vinyl ketone (EVK, 0.064 mL, 0.646 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.013 mL, 0.086 mmol). The resulting solution was stirred under a nitrogen atmosphere and heated in an oil bath at 60° C. After 24 hour, more EVK (0.064 mL) and DBU (0.013 mL) were added and the solution was heated an additional 24 hours at 60° C. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (10 mL) containing 2N HCl (1 mL). The organic phase was washed with brine (5 mL), dried over MgSO4, filtered, and evaporated under vacuum to provide crude 2-butyl-5-methoxy-4-methyl-2-(3-oxopentyl)-1-indanone.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1>FC(F)(F)C(O)=O.CO>[CH2:1]1[C@@H:14]2[C@@H:6]([NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[CH2:5][CH2:4][NH:3][CH2:2]1
Reactant: c1ccc2c3c([nH]c2c1)CCNCC3
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: c1ccc2c(c1)N[C@H]1CCNCC[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.93 g, 5.0 mmol) in trifluoroacetic acid (17 mL) was cooled to 0° C., and treated with a freshly prepared solution of Na(CN)BH3 (1.57 g, 25 mmol) in MeOH (4 mL). The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h, then treated with water (75 mL), stirred for an additional 15 minutes before adjusting the pH to 14 with 45% KOH (aqueous). The resulting solution was extracted with EtOAc (3×40 mL), and the combined organic extracts were washed once with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a yellow syrup. The crude product was purified by chromatography and using ethanol:ammonia:dichloromethane (15:1.5:83.5) and trituration of the resulting material gave the title compound (0.64g) as an off-white solid: mp 102-114° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[N:26][N:27]([CH:29]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]2)[CH:28]=1>CO.O>[C:19]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:6]2[C:5]([Cl:22])=[CH:4][N:3]=[C:2]([NH:23][C:24]3[CH:25]=[N:26][N:27]([CH:29]4[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]4)[CH:28]=3)[N:7]=2)[CH2:18][CH2:17]1)(=[O:20])[NH2:21]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)C1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)C1

Procedure:
A stirred solution of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.150 g, 0.446 mmol), 4-amino-1-(1-Boc-pyrrolidin-3-yl)-1H-pyrazole (0.225 g, 0.892 mmol) in MeOH (10 mL) and water (1.0 mL) was heated at 70° C. for 2 days. Additional 4-amino-1-(1-boc-pyrrolidin-3-yl)-1H-pyrazole (0.125 g, 0.446 mmol) was added and the mixture was heated for a further 16 hours at reflux. After cooling the solvent was removed to afford a crude red oil which was purified by silica gel column chromatography (0-100% EtOAc in cyclohexane) to give the title compound A21 as a red oil (0.164 g, 67% yield). LCMS-C: rt 5.51 min; m/z 551.9 [M+H]+.
Reaction SMILES: [CH:1]1([C@H:4]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@@H:5]([OH:10])[C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.[C:19](OC)([CH3:21])=[CH2:20].[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1>C1C=CC=CC=1>[C:15]([O:14][C:12]([N:11]1[C@@H:4]([CH:1]2[CH2:3][CH2:2]2)[C@H:5]([C:6]([O:8][CH3:9])=[O:7])[O:10][C:19]1([CH3:21])[CH3:20])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C1CC1
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 2.63 g of methyl (2R,3S)-3-cyclopropyl-3-tert-butoxycarbonylamino-2-hydroxypropionate in 60 ml of benzene are added 1.94 ml of isopropenylmethylether and 0.25 g of p-toluenesulfonic acid pyridinium salt. The mixture is stirred at room temperature for one hour, and then refluxed for 40 minutes. After the mixture is cooled, 1.94 ml of isopropenylmethylether is added to the reaction mixture. The mixture is stirred at room temperature for 10 minutes, refluxed for 40 minutes, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=8:1) to give 2.69 g of methyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-cyclopropyl-5-oxazolidinecarboxylate.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=1[CH:35]1[CH2:38][CH2:37][CH2:36]1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:22][CH2:23][N:24]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH:35]3[CH2:38][CH2:37][CH2:36]3)[CH2:25][CH2:26]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncnc(Cl)c1C1CCC1
Reactant: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Product: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C4CCC4)CC3)n2)ccn1

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “1” by using 4-[1-(2-azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-isopropyl-pyridine and 6-chloro-5-cyclobutyl-pyrimidin-4-ylamine as the starting materials. LC-MS (M+H=501, obsd=501).