Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[Cl:21].ClC(OCC)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:10])=[CH:18][C:19]=1[Cl:20]
Reactant: Nc1c(Cl)cc(C(=CC(=O)O)c2ccc(Br)cc2)cc1Cl
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc(C(=CC(=O)N2CCOCC2)c2ccc(Br)cc2)cc1Cl

Procedure:
This compound was prepared from 4-amino-β-(4'-bromophenyl)-3,5-dichloro-cinnamic acid (isomer ratio A:B=1:2.5), ethyl chloroformate, triethylamine and morpholine analogous to Example 1(c).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:36])[C:24]2[C:16](=[CH:17][C:18]3[NH:19][C:20]([S:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[N:21][C:22]=3[CH:23]=2)[C:15]([CH3:34])([CH3:33])[C:14]1=[O:35]>C(OCC)(=O)C.C(Cl)Cl>[CH3:12][C:13]1([CH3:36])[C:24]2[C:16](=[CH:17][C:18]3[NH:19][C:20]([S:25]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[O:9])=[N:21][C:22]=3[CH:23]=2)[C:15]([CH3:34])([CH3:33])[C:14]1=[O:35]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(SCc4ccccn4)nc3cc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S(=O)Cc4ccccn4)nc3cc21
Reaction time: 3 h
Yield: 42.3 %

Procedure:
31 ml of a 10% solution of m-chloroperbenzoic acid in ethyl acetate were added dropwise with intensive stirring at 0°-5° C. to 6.16 g of 5,7-dihydro-5,5,7,7-tetramethyl-2-[(2-pyridylmethyl)thio]indeno(5,6-d)-imidazol-6(1H)-one, dissolved in 100 ml of methylene chloride, in a 250 ml sulfonation flask equipped with stirrer, thermometer, dropping funnel and calcium chloride tube. After stirring at 0°-5° C. for 3 hours, the mixture was poured into 1 l of methylene chloride, it was washed twice with 250 ml of 2N soda, then neutral with water, dried over sodium sulfate and evaporated in vacuo. Crystallization of the residue from acetonitrile gave 2.7 g (42.3% of theory) of 5,7-dihydro-5,5,7,7-tetramethyl-2-[(2-pyridylmethyl)sulfinyl]indeno(5,6-d)imidazol-6(1H)-one of melting point 201°-203° C.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:32])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:50])[C@@H:15]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si](C(C)(C)C)(C)C)[CH2:36]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:32])[CH:21]([O:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:50])[C@@H:15]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([OH:42])[CH2:36]2)=[CH:10]1
Reactant: CCC(Oc1ccc(F)cc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1ccc(F)cc1)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 36.4 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 1.20 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(4-fluorophenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyan-2-one [prepared as described in Example 22, above] and 24.6 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.30 g of the title compound, melting at between 149° and 150° C.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12]C)[CH2:6][CH2:5]1.[CH2:37]([N:39]1[CH:44]=[CH:43][C:42](I)=[CH:41][C:40]1=[O:46])[CH3:38]>>[CH2:37]([N:39]1[CH:44]=[CH:43][C:42]([C:17]2[CH:16]=[CH:15][C:14]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:36])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:19][CH:18]=2)=[CH:41][C:40]1=[O:46])[CH3:38]
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CCn1ccc(I)cc1=O
Product: CCn1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 1-ethyl-4-iodopyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.228 min, m/z=971.4; 1H NMR (CDCl3) 1.10 (s, 3H), 1.14 (s, 3H), 1.36 (m, 3H), 1.53 (d, 3H), 2.17 (s, 2H), 2.21-2.32 (m, 2H), 2.32-2.48 (m, 1H), 2.88 (m, 1H), 4.00 (m, 2H), 5.68 (m, 1H), 6.39 (d, 1H), 6.78 (s, 1H), 6.99 (d, 2H), 7.27-7.38 (m, 8H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(=O)C.[F:27][C:28]([F:48])([F:47])[O:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][CH2:39][C:38]3([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[C:37]2=[O:46])=[CH:32][CH:31]=1.[CH:49]([O:52][CH2:53][C:54](O)=[O:55])([CH3:51])[CH3:50]>>[CH:49]([O:52][CH2:53][C:54]([N:43]1[CH2:42][CH2:41][C:38]2([C:37](=[O:46])[N:36]([C:33]3[CH:34]=[CH:35][C:30]([O:29][C:28]([F:27])([F:47])[F:48])=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)[CH2:45][CH2:44]1)=[O:55])([CH3:51])[CH3:50]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: CC(C)OCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Product: CC(C)OCC(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 13 step A (using TBTU instead of BOP as the coupling reagent) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and isopropoxy-acetic acid. Off-white solid. MS (ESI): 415.3 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21]([N:23]([CH:37]([CH3:39])[CH3:38])[C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]3)=[O:22])[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:41])([CH3:40])[C:8]1=[O:42])C.[OH-].[Na+].CO>C1COCC1>[C:33]([O:32][C:30]([N:26]1[CH2:27][CH2:28][CH2:29][C@@H:24]([N:23]([CH:37]([CH3:39])[CH3:38])[C:21]([C:14]2[C:15]([C:17]([F:18])([F:20])[F:19])=[CH:16][C:11]3[O:10][C:9]([CH3:40])([CH3:41])[C:8](=[O:42])[N:7]([CH2:6][CH2:5][C:4]([OH:43])=[O:3])[C:12]=3[CH:13]=2)=[O:22])[CH2:25]1)=[O:31])([CH3:34])([CH3:35])[CH3:36]
Reactant: CCOC(=O)CCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCC(=O)O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl (3R)-3-[{[4-(3-ethoxy-3-oxopropyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (350 mg) were added a 2N NaOH aqueous solution (5 ml), MeOH (5 ml) and THF (5 ml), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was concentrated, and thereto was added dropwise a 2N aqueous hydrochloric acid solution. The precipitated crystals were extracted with ethyl acetate. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue (260 mg) was used in the subsequent reaction without a further treatment.
Reaction SMILES: [C:1]([C:4]1[S:13][C:12]2[S:11][CH2:10][CH2:9][N:8]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:20][CH2:19]3)[C:7](=[O:30])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].OO.S([O-])(O)=[O:34].[Na+]>C(O)(=O)C>[C:1]([C:4]1[S:13][C:12]2[S:11](=[O:34])[CH2:10][CH2:9][N:8]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][N:21]([C:24]4[N:25]=[CH:26][CH:27]=[CH:28][N:29]=4)[CH2:22][CH2:23]3)[C:7](=[O:30])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c(s1)SCCN(CCCCN1CCN(c3ncccn3)CC1)C2=O
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)c1cc2c(s1)S(=O)CCN(CCCCN1CCN(c3ncccn3)CC1)C2=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2.0 g of 7-acetyl-2,3-dihydro-4-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]thieno[3,2-f]-1,4-thiazepin-5(4H)-one in 20 ml of acetic acid was added to 1.0 g of 30% hydrogen peroxide and the mixture was stirred for 20 hours at room temperature. Then, the mixture was poured into ca. 3% aqueous sodium hydrogen sulfite solution and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and the solvent was distilled off. The resulting crude crystals were recrystallized from ethanol to give 1.5 g of 7-acetyl-2,3-dihydro-4-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]thieno[3,2-f]-1,4-thiazepin-5(4H)-one 1-oxide as white crystals, melting at 103°-106° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH2:23])=[N:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:33][CH2:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.CO>O1CCOCC1.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:39](=[O:40])[C:38]4[CH:42]=[CH:43][C:35]([CH2:34][Cl:33])=[CH:36][CH:37]=4)=[N:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(N)nc12
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Yield: 74 %

Procedure:
To a solution of 0.35 g (0.97 mMol) 4-(2-amino-4-methoxy-benzothiazol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 20 ml dioxane were added 0.2 ml triethyl amine, 12 mg DMAP and 0.238 g (1.26 mMol) 4-chloromethyl-benzoyl chloride, dissolved in 1 ml of dioxane. The reaction mixture was heated to reflux for 3 h. Then 5 ml methanol were added. The solvent was evaporated to dryness, the residue taken up in ethyl acetate and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane 1:1) to yield 0.37, (74%) 4-[2-(4-chloromethyl-benzoylamino)-4-methoxy-benzothiazol-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a white foam. ES-MS m/e (%): 514 ([M+H]+, 100).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2.[OH:16][CH2:17][CH2:18]CCCC12CC(=O)CC1CCC2.O>C(O)(=O)C>[C:17]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2)(=[O:16])[CH3:18]
Reactant: O=C1CC2CCC(CCCCCO)C2C1
Reactant: O=C1CC2CCCC2(CCCCCO)C1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCCCCCC1CCC2CC(=O)CC12
Temperature: 75 °C

Procedure:
The starting material 2-(5-hydroxypent-1-yl)bicyclo[3.3.0]octan-7-one {hexahydro-4-(5-hydroxypentyl)-2(1H)-pentalenone} (0.8 g, 3.8 mmoles) is diluted with glacial acetic acid (7 ml). The reaction is stirred and heated in a 75° C. oil bath for 24 hours, after which time water (20 ml) is added and the reaction partitioned between ether. The ether layer is separated and the aqueous phase extracted again with ether (2×50 ml). The extracts and the organic phase are combined and neutralized with saturated sodium bicarbonate. The organic phase is dried over anhydrous magnesium sulfate and the remained solvent removed under vacuum leaving a pale yellow oil. The product is kugelrohred under reduced pressure leaving a clear, colorless oil (0.5 g, 2.0 mmoles).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[N:3]=1.[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]1([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41]1)#[CH:33].F[B-](F)(F)F.CCN(C(C)C)C(C)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:43]([C:40]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:32]#[C:33][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[N:17][CH:18]=3)[N:3]=2)[CH2:41][CH2:42]1)(=[O:44])[NH2:45]
Reactant: C#Cc1ccccc1C1(C(N)=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a mixture of tert-butyl 4-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate A70 (0.208 g, 0.453 mmol), 1-(2-ethynylphenyl)cyclopropanecarboxamide K6 (0.079 g, 0.42 mmol), CuI (0.003 g, 0.02 mmol), PdCl2(PPh3)2 (0.017 g, 0.024 mmol) and t-Bu3PH.BF4 (0.009 g, 0.03 mmol) under a nitrogen atmosphere was added dioxane (6.0 mL) and DIPEA (0.23 mL, 1.3 mmol). The mixture was stirred at 85° C. for 4 hours and then concentrated under reduced pressure. Purification by silica gel column chromatography (Biotage Isolera, 0-100% EtOAc in Petroleum Benzine 40-60° C., 0-20% MeOH in EtOAc) gave the title compound A78 (0.118 g, 46%). LCMS-D: rt 3.645 min; m/z 607.4 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([P:6]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])(=[O:10])[O:7][CH2:8][CH3:9])[CH2:3][C:4]#[N:5].N.[H][H]>C(O)C.[Ni]>[NH2:5][CH2:4][CH2:3][CH:2]([P:6]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])(=[O:10])[O:7][CH2:8][CH3:9])[CH3:1]
Reactant: CCOC(OCC)P(=O)(OCC)C(C)CC#N
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(OCC)C(C)CCN

Procedure:
A solution of 17.0 g of ethyl 1-methyl-2-cyanoethyl(diethoxymethyl)phosphinate in 150 ml of ethanol is added to 155.0 g of an 8% solution of ammonia in ethanol. To this are added 10 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure and the crude product is distilled under reduced pressure to give ethyl 3-amino-1-methylpropyl(diethoxymethyl)phosphinate, b.p. 140° C./0.01 mbar, 31 p=+47.0 and +46.7 ppm (CDCl3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH2:12])[NH:8][C:5]2=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][C:53]=1[C:54]([N:56]1[CH2:60][CH:59]=[CH:58][CH2:57]1)=[O:55])[C:48](O)=[O:49]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH:12][C:48](=[O:49])[C:47]3[CH:51]=[CH:52][C:53]([C:54]([N:56]4[CH2:57][CH:58]=[CH:59][CH2:60]4)=[O:55])=[C:45]([CH3:44])[CH:46]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CC=CC1
Reactant: NCc1nc2cc(Br)cnc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCc2nc3cc(Br)cnc3[nH]2)ccc1C(=O)N1CC=CC1

Procedure:
Prepared analogously to Example 1g from C-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)methylamine, TBTU, diisopropylethylamine, and 3-methyl-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid in tetrahydrofuran. Purification is effected by chromatography on silica gel (gradient: dichloromethane/ethanol=100:0□80:20). Yield: 240 mg (96%); Rf value: 0.68 (silica gel; dichloromethane/ethanol=8:2+2% ammonia solution); C20H18BrN5O2 (440.30); mass spectrum: (M+H)+=440/442 (bromine isotope).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:12])=[O:13])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)c1ccc(N(C)S(C)(=O)=O)cc1
Yield: 64.1 %

Procedure:
Ex-101A: A solution of N-(4-acetyl-phenyl)-methanesulfonamide (Ex-100A, 2.0 g, 9.4 mmol) in anhydrous DMF (300 mL) was treated with potassium carbonate (2.59 g, 18.8 mmol), followed by the addition of methyl iodide (5.85 mL, 94 mmol). The reaction mixture refluxed for two hours and was then treated with more methyl iodide (5.85 mL, 94 mmol). The reaction refluxed for another two hours, and reaction completeness was confirmed by HPLC analysis. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic phase was collected, dried over sodium sulfate, and concentrated to a clear oil with residual DMF. Water (25 mL) was added to precipitate a white solid. The white solid was then filtered and dried by vacuum oven at 20° C. (−20 mm Hg) to give 1.37 g (64%) of N-(4-acetyl-phenyl)-N-methyl-methanesulfonamide. 1H-NMR (CDCl3) δ 7.88 (d, 2H), 7.48 (d, 2H), 3.38 (s, 3H), 2.86 (s, 3H), 2.60 (s, 3H). HRMS m/z: calc. 530.1307, found 530.1313.
Reaction SMILES: [CH3:1][C:2]([C:32]([O:34]C)=[O:33])([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[NH:3][C:4]([O:6][CH:7]1[CH:14]2[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)=[O:5].O.[OH-].[Li+]>O1CCOCC1.O>[CH3:1][C:2]([C:32]([OH:34])=[O:33])([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:23]=1)[NH:3][C:4]([O:6][CH:7]1[CH:8]2[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][CH:14]1[CH2:15]3)[CH2:16]2)=[O:5]
Reactant: COC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC1C2CC3CC(C2)CC1C3
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(Cc1ccc(OCc2ccccc2)cc1)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
To a stirred solution of methyl α-methyl-O-(phenylmethyl)-N-[(tricyclo[3.3.1.13,7 ]dec-2-yloxy)-carbonyl]-DL-tyrosinate (1.10 g, 0.0023 mol) in 8.8 mL dioxane and 4.4 mL water, lithium hydroxide monohydrate (0.145 g, 0.003 mmol, 1.5 eq) was added. This reaction mixture was then stirred for 48 hours at room temperature. The reaction mixture was then concentrated in vacuo and the resulting white syrup was diluted with 20 mL H2O. Thisbasic solution (pH 13) was then acidified (pH 2) with 1 mL 10% HCl, upon which white solid precipitated. This acidified aqueous suspension was thenextracted three times each with ether. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the desired product (0.78 g, 0.0016 mmol, 73%). MS: 464.3 (MH+); 463.3 (M+).
Reaction SMILES: COCO[C:5]1[C:14](C)=[C:13](C)[C:12]2OC(C)(C)[CH2:9][CH2:8][C:7]=2[C:6]=1C=O.C([O-])(=O)C.[NH4+].[N+:26](C)([O-:28])=[O:27]>CCOC(C)=O>[N+:26]([CH:9]=[CH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:5][CH:6]=1)([O-:28])=[O:27]
Reactant: C[N+](=O)[O-]
Reactant: COCOc1c(C)c(C)c2c(c1C=O)CCC(C)(C)O2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])C=Cc1ccccc1
Temperature: 80 °C

Procedure:
6-(Methoxymethoxy)-2,2,7,8-tetramethylchroman-5-carbaldehyde (500 mg, 1.7 mmol) and ammonium acetate (157 mg, 1.7 mmol) were taken up in nitromethane (11.6 mL) and the mixture was warmed to 80° C. for 1.5 hrs. After this time, the reaction was judged to be complete and the mixture was diluted in EtOAc (75 mL), washed once with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (gradient elution 0→15% EtOAc/Heptane) afforded the yellow solid nitrostyrene intermediate (500 mg). 1H NMR (CDCl3, 400 MHz) 8.30 (d, 2H), 7.80 (d, 2H), 4.82 (s, 2H), 3.76 (s, 3H), 2.78 (t, 2H), 2.20 (s, 3H), 2.12 (s, 3H), 1.80 (t, 2H), 1.26 (s, 6H) ppm. The intermediate compound was dissolved in 5 mL THF and added dropwise over 30 min to a stirring suspension of LiAlH4 (400 mg, 10 mmol) in 3 mL THF at 0° C. After addition was complete, the mixture was stirred at 50° C. After 5 hr total, excess reagent was quenched by addition of 3 g sodium sulfate dodecylhydrate. The resulting suspension was stirred for 30 min, during which time the grey color turned to white. Subsequently, the suspension was filtered, and the filtrate concentrated in vacuo to provide 2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine as a colorless oil, 450 mg. 1H NMR (CD3OD, 400 MHz) 4.84 (s, 2H), 3.60 (s, 3H), 2.80 (m, 4H), 2.70 (t, 2H), 2.14 (s, 3H), 2.06 (s, 3H), 1.78 (t, 2H), 1.22 (s, 3H), 1.20 (s, 3H) ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([S:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[C:6]#[N:7].[CH3:26][CH:27]1[C:36]2[C:31](=[CH:32][C:33]([OH:38])=[C:34]([OH:37])[CH:35]=2)[CH2:30][CH2:29][NH:28]1>>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:5]([S:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)([CH2:4][CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][C:31]3[C:36](=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=3)[CH:27]2[CH3:26])[C:6]#[N:7])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COc1ccc(C(C#N)(CCCCl)Sc2ccc(C)cc2)cc1OC
Reactant: CC1NCCc2cc(O)c(O)cc21
Product: COc1ccc(C(C#N)(CCCN2CCc3cc(O)c(O)cc3C2C)Sc2ccc(C)cc2)cc1OC
Yield: 18.3 %

Procedure:
The procedure of Example 3 is repeated using 1.0 g of α-(3-chloropropyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 0.76 g of 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline. This affords 0.253 g of the desired product as a beige gum.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([CH2:37][OH:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH3:2].[C:39](Cl)(=[O:42])[CH2:40][CH3:41]>>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([CH2:37][O:38][C:39](=[O:42])[CH2:40][CH3:41])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CCOc1cc(CC(=O)NC(CO)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1
Product: CCOc1cc(CC(=O)NC(COC(=O)CC)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1

Procedure:
Prepared analogously to Example 37 from benzyl 2-ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate with propionyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:20]([O:22][CH2:23][C:24](O)=O)[CH3:21].[OH-].[NH4+]>O>[CH2:20]([O:22][CH2:23][C:24]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:21]
Reactant: CCOCC(=O)O
Reactant: Nc1cnc2ccccc2c1NCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1Cc1ccccc1
Temperature: 120 °C

Procedure:
3-Amino-4-(phenylmethylamino)quinoline (4 g, mmol) was combined with ethoxyacetic acid (4.5 mL, mmol) and heated at 120° C. for about 3 hours. The reaction mixture was cooled to room temperature, diluted with water and then made basic with ammonium hydroxide. The resulting precipitate was collected to provide 5.3 g of the desired product as a solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.