Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:30]([Br:31])=[CH:29][C:5]([CH2:6][C@H:7]([C:26]([OH:28])=O)[NH:8]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[CH:4][C:3]=1[Br:32].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][C:75]([CH3:92])([O:77][C:78]([N:80]1[CH2:85][CH2:84][CH:83]([CH:86]2[CH2:91][CH2:90][NH:89][CH2:88][CH2:87]2)[CH2:82][CH2:81]1)=[O:79])[CH3:76].C(NCC)C>O1CCCC1>[NH2:1][C:2]1[C:3]([Br:32])=[CH:4][C:5]([CH2:6][C@H:7]([C:26]([N:89]2[CH2:88][CH2:87][CH:86]([CH:83]3[CH2:82][CH2:81][N:80]([C:78]([O:77][C:75]([CH3:92])([CH3:76])[CH3:74])=[O:79])[CH2:85][CH2:84]3)[CH2:91][CH2:90]2)=[O:28])[NH2:8])=[CH:29][C:30]=1[Br:31]
Reactant: Nc1c(Br)cc(C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCNCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(C(=O)[C@H](N)Cc3cc(Br)c(N)c(Br)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5.60 g (0.01 mol) of 4-amino-3,5-dibromo-N -(9-fluorenylmethoxycarbonyl)-D-phenylalanine, 1.35 g (0.01 mol) HOBt, 3.21 g (0.01 mol) TBTU, 1.29 g (0.01 mol) DIEA, 2.68 g (0.01 mol) 4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-piperidine and 150 ml of tetrahydrofuran was stirred for 2 hours at room temperature. After the reaction was complete 20 ml of diethylamine were added and the mixture was stirred for a further 18 hours at room temperature. The reaction mixture was evaporated down in vacuo, the residue was taken up in 200 ml of dichloromethane and washed successively with 100 ml of saturated sodium chloride solution and saturated sodium hydrogen carbonate solution and dried over magnesium sulphate. The reddish oil remaining after elimination of the solvent was purified by column chromatography on silica gel (30-60 μm) using firstly dichloromethane, then FM4 as eluant. The title compound was obtained in the form of a colourless amorphous substance and in a yield of 4.31 g (73.3% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([OH:33])[CH2:21][CH2:22][C:23]4[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=4C(OC)=O)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:34][Mg+].[Br-].[CH3:37][C:38]([OH:40])=O>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([OH:33])[CH2:21][CH2:22][C:23]4[CH:24]=[CH:29][CH:30]=[CH:31][C:32]=4[C:38]([OH:40])([CH3:37])[CH3:34])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: C[Mg+]
Reactant: CC(=O)O
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the hydroxyester of Step 2 (38.68 g, 84.36 mmol) in 600 mL of toluene at 0° C. was added slowly 225 mL of 1.5M MeMgBr in toluene:THF 3:1 and the mixture was stirred at r.t. for 4 h. It was then poured into 2 L cold 12% NH4OAc and 25 mL of AcOH were added. The products were extracted in EtOAc, washed with brine, dried over Na2SO4 and concentrated. Flash chromatography of the residue with EtOAc:toluene 15:85 and 25:75 afforded first the methyl ketone derivative, then the title compound.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][NH2:15]>>[CH3:14][NH:15][C@H:10]1[CH2:11][CH2:12][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CN
Product: CN[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
from 4-phenylcyclohexanone and methylamine. Melting point: 40° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([N:23](C)[CH3:24])[C:13]([O:21][CH3:22])=[C:14]([CH:20]=2)[N:15]([CH3:19])[C:16](=O)C)=[CH:4][N:3]=1.Cl>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([NH:23][CH3:24])[C:13]([O:21][CH3:22])=[C:14]([N:15]([CH3:19])[CH3:16])[CH:20]=2)=[CH:4][N:3]=1
Reactant: COc1c(N(C)C)cc(Cc2cnc(N)nc2N)cc1N(C)C(C)=O
Agent: Cl
Product: CNc1cc(Cc2cnc(N)nc2N)cc(N(C)C)c1OC

Procedure:
4.0 G. of 5'-[(2,4-diamino-5-pyrimidinyl)methyl]-3'-dimethylamino-2'-methoxy-N-methylacetanilide (prepared as described in the first paragraph of Example 2) and 100 ml. of 1-N hydrochloric acid were boiled under reflux for 2 hours. After neutralization and evaporation in vacuo, purification of the residue over silica gel with methylene chloride/propanol (8:2) and recrystallization from ethanol, there was obtained 2,4-diamino-5-[3-dimethylamino-4-methoxy-5-(methylamino)benzyl]pyrimidine, having a melting point of 183° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.[CH3:34][N:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:36](Cl)=[O:37]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:36]([N:35]([CH3:34])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:37])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Solvent: c1ccncc1
Product: COc1cc(OC(=O)N(C)c2ccccc2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 100 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A mixture 8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 11, 25.4 mg, 0.0564 mmol) and N-methyl-N-phenylcarbamoyl chloride (20.4 mg, 0.120 mmol) was dissolved in pyridine (1 mL), and stirred for 2 hours at 100° C. The reaction mixture was concentrated, and then the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (28.7 mg) as a pale yellow amorphous product. (Yield 87%)
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][CH3:27])=[C:21]([CH:25]=1)[C:22](Cl)=[O:23]>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][CH3:27])=[C:21]([CH:25]=1)[C:22]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1)=[O:23]
Reactant: CCOC(=O)CCc1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)Nc1ccc(CCC(=O)O)cc1

Procedure:
By the reaction of ethyl β-(4-aminophenyl)-propionate hydrochloride with 5-chloro-2-methoxybenzoyl chloride. there is obtained β-[4-(5-chloro-2-methoxybenzamido)-phenyl]-propionic acid; m.p. 188°-190° C., after recrystallization from ethanol.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:54])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3].[C:55]([O:59][C:60]([NH:62][C@H:63]([C:68]([O:70]C(C)(C)C)=O)[CH2:64][C:65]([OH:67])=[O:66])=[O:61])([CH3:58])([CH3:57])[CH3:56]>ClCCl>[C:55]([O:59][C:60]([NH:62][C@H:63]([C:68]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:54])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3])=[O:70])[CH2:64][C:65](=[O:66])[O:67][C:6]([CH3:11])([CH3:7])[CH3:4])=[O:61])([CH3:56])([CH3:57])[CH3:58]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Yield: 27 %

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-oleamide and N-tert-butyloxycarbonyl-O-tert-butyl-L-aspartic acid. Yield 27%. [α]D =-1.5° (c=0.55, dichloromethane).
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1.O>C(O)(=O)C>[N:4]1([C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]#[N:9])[CH:12]=[CH:16][CH:15]=[CH:14]1
Reactant: N#Cc1ccccc1N
Reactant: COC1CCC(OC)O1
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccccc1-n1cccc1

Procedure:
Anthranilonitrile (10.0 grams, 85.0 mmol) was dissolved in 350 mL of acetic acid. To this was added 2,5-dimethoxytetrahydrofuran (11.0 mL, 85.0 mmol). This was stirred at reflux for 2 hours after which time the reaction mixture was pored into water and the product extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and chromatographed on a silica gel column using a mobile phase of 1:1 dichloromethane-hexane to afford the title compound as a white solid. NMR confirms structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[Cl:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][NH2:28])[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][NH:28][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCCc1cccc(Cl)c1
Product: O=C(NCCc1cccc(Cl)c1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-[2-(3-chlorophenyl)ethyl]-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.5 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.75 mmol of 2-(3-chlorophenyl)ethylamine. LC/MS [10.47 min; 496 (M+1)]
Reaction SMILES: [Na+:1].[Na+].[O:3]([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[N:37][C:38]2[C:47]([NH2:48])=[CH:46][CH:45]=[C:44]3[C:39]=2[CH:40]=[CH:41][C:42]([S:49]([O-:52])(=[O:51])=[O:50])=[CH:43]3)=[CH:32][C:31]=1[N+:53]([O-])=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:17]3)=[CH:6][C:5]=1[N+:27]([O-])=O.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].O>C(O)(=O)C>[Na+:1].[Na+:1].[O:3]([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[N:37][C:38]2[C:47]([NH2:48])=[CH:46][CH:45]=[C:44]3[C:39]=2[CH:40]=[CH:41][C:42]([S:49]([O-:52])(=[O:51])=[O:50])=[CH:43]3)=[CH:32][C:31]=1[NH2:53])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:17]3)=[CH:6][C:5]=1[NH2:27]
Reactant: Nc1ccc2cc(S(=O)(=O)[O-])ccc2c1N=Nc1ccc(Oc2ccc(N=Nc3c(N)ccc4cc(S(=O)(=O)[O-])ccc34)cc2[N+](=O)[O-])c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [S-2]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(N=Nc2c(N)ccc3cc(S(=O)(=O)[O-])ccc23)ccc1Oc1ccc(N=Nc2c(N)ccc3cc(S(=O)(=O)[O-])ccc23)cc1N

Procedure:
A mixture of 4.0 g. of 5,5'-[oxybis(2-nitro-p-phenyleneazo)]bis-[6-amino-2-naphthalenesulfonic acid] disodium salt and 4.0 g. of sodium sulfide nonahydrate is dissolved in 50 ml. of water by heating on a steam bath for 15 minutes. The solution is cooled and 1.6 ml. of acetic acid is added. The mixture is then filtered through diatomaceous earth. The product is salted out of the filtrate with 25 g. of sodium acetate trihydrate at room temperature, filtered and washed with a small amount of 33% aqueous solution of sodium acetate trihydrate then with ethanol and ether. The product is dissolved in 30 ml. of hot water and filtered through diatomaceous earth. An 18 g. portion of sodium acetate trihydrate is added to the filtrate and this mixture is filtered and the product is washed with ethanol and ether to give 5,5'-[oxybis(2-amino-p-phenyleneazo)]bis-[6-amino-2-naphthalenesulfonic acid] disodium salt.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.[CH2:28]([OH:32])[CH2:29][CH:30]=[CH2:31]>C(N(CC)CC)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:21](/[CH:31]=[CH:30]/[CH2:29][CH2:28][OH:32])=[CH:22][CH:23]=1
Reactant: C=CCCO
Reactant: Clc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OCC/C=C/c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 52 %

Procedure:
To a suspension of triphenyl phosphine (2.1 g, 8.0 mmole) in 300 ml of triethylamine and 30 ml of acetonitrile under nitrogen is added successively palladium (II) acetate (0.45 g, 2.0 mmole), 1-bromo-4-chlorobenzene (19.1 g, 110 mmole) and 3-buten-1-ol (7.21 g, 100 mmole) in a pressure tube. The tube is sealed and heated in an oil bath to 100° C. for 24 hr. The tube is opened under nitrogen, charged with additional palladium (II) acetate, resealed and heated 20 hr longer at 100°-120° C. The mixture is cooled, vented to nitrogen and partitioned between 300 ml of 2N hydrochloric acid and ether. The layers are separated and the aqueous layer is extracted with two additional volumes of ether. The combined ether extracts are washed with 2×100 ml portions of 2N hydrochloric acid and then dried over sodium sulfate. The filtered ether extract is concentrated under vacuum to give 12.7 g of crude product which is purified by chromatography on silica gel using toluene eluent. There is obtained 9.5 g of the title compound. Rf =0.77 (silica gel, toluene).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25].[CH:30]1([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:32][CH2:31]1>>[CH:30]1([C:33]2[CH:39]=[CH:38][C:36]([N:37]3[CH2:13][CH2:12][C:6]4([CH2:7][CH2:8][N:9]([S:24]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=5[C:17]([F:29])([F:28])[F:16])(=[O:26])=[O:25])[CH2:10][CH2:11]4)[C:4]3=[O:5])=[CH:35][CH:34]=2)[CH2:32][CH2:31]1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: Nc1ccc(C2CC2)cc1
Product: O=C1N(c2ccc(C3CC3)cc2)CCC12CCN(S(=O)(=O)c1ccccc1C(F)(F)F)CC2

Procedure:
Off-white solid. MS (ESI): 479.16 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethyl-benzenesulfonyl chloride and 4-cyclopropyl-aniline.
Reaction SMILES: [OH:1][C:2]([CH3:10])([C:6]([F:9])([F:8])[F:7])[C:3]([OH:5])=[O:4].C1([C@@H](N)C)C=CC=CC=1>CO>[OH:1][C@@:2]([CH3:10])([C:6]([F:9])([F:8])[F:7])[C:3]([OH:5])=[O:4]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Agent: C[C@H](N)c1ccccc1
Solvent: CO
Product: C[C@@](O)(C(=O)O)C(F)(F)F

Procedure:
(R/S)-2-Hydroxy-2-methyl-3,3,3-trifluoropropanoic acid was resolved according to the resolution method described in European Patent Application No. EP 524781 (described for the preparation of the (S)-(−)-acid) except that (1S,2R)-norephedrine was used in place of (1R,2S)-norephedrine or (S)-(−)-1-phenylethylamine to yield the title compound, [α]D20 +18.1° C. (c, 8.8 in MeOH); NMR analysis of the acid in the presence of (R)-(+)-1-phenylethylaine gave an enantiomerical purity of >98%. NMR (CDCl3): 1.27 (s, 3H) for the (R)-enantiomer, 1.21 (s, 3H) for the (S)-enantiomer.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]2[C:12](=[C:14]([C:18]([OH:20])=O)[CH:15]=[CH:16][CH:17]=2)[N:13]=1.Cl.Cl.[NH2:24][C@H:25]1[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:27]12[CH2:32][CH2:31][CH:30]([CH2:29][CH2:28]1)[C@H:25]([NH:24][C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:11]3[O:10][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[N:2]([CH3:1])[CH3:21])=[N:13][C:12]=13)=[O:20])[CH2:26]2
Reactant: CN(C)c1ccccc1-c1nc2c(C(=O)O)cccc2o1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)c1ccccc1-c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.7 %

Procedure:
A mixture of 2-(2-(dimethylamino)phenyl)benzo[d]oxazole-4-carboxylic acid (100 mg, 0.35 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (70 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg, 0.70 mmol) and 1-hydroxybenzotriazole (95 mg, 0.70 mmol) in DMF (1 mL) was stirred for 5 min at room temperature, then triethylamine (0.19 mL, 1.4 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2-dimethylaminophenyl)benzoxazole-4-carboxamide (46 mg, 34%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.60 (d, J=7.0 Hz, 1H), 8.19 (dd, J=7.5, 1.0 Hz, 1H), 7.99 (dd, J=8.0, 2.0 Hz, 1H), 7.71 (dd, J=8.0, 1.0 Hz, 1H), 7.49-7.42 (m, 2H), 7.13 (d, J=8.5 Hz, 1H), 7.03 (t, J=8.5 Hz, 1H), 4.28-4.26 (m, 1H), 3.49 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.10-2.85 (m, 4H), 2.85 (s, 6H), 2.77 (dd, J=14.0, 4.5 Hz, 1H), 2.15-2.11 (m, 1H), 2.04-1.98 (m, 1H), 1.78-1.70 (m, 2H), 1.60-1.51 (m, 1H); MS (ESI+) m/z 391 (M+H); HPLC>99% (AUC), tR=12.81 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.C(=O)(O)[O-].[Na+].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>C(OCC)(=O)C>[C:31]1([O:30][C:28](=[O:29])[NH:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[N:5]=[C:4]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:3]([O:2][CH3:1])=[CH:8][N:7]=3)=[CH:10][CH:11]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1cnc(-c2ccc(N)cc2)nc1N1CCOCC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cnc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc1N1CCOCC1
Reaction time: 0.08 h
Yield: 40.5 %

Procedure:
A mixture of 4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine (1.50 g, 1.0 eq.) and sodium bicarbonate solution (6 ml) in ethyl acetate (6 ml) stirring 5 min. After dropping phenyl chloroformate (0.98 ml, 1.2 eq) for 4 hrs at room temperature. The resultant mixture extracted with EA and the combined organic layers were washed with brine and dried in vacuo to give a light brown solid (1.80 g, 40.5%) as the product.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1>C1COCC1>[O:15]=[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C1CCC(=O)O1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)NCc1ccccc1
Yield: 52.7 %

Procedure:
A mixture of benzyl amine (10.7 g) and succinic anhydride (10 g) was stirred in THF (1 liter) for 2 days. The solid was filtered and dissolved in 1N NaOH (110 ml). The aqueous phase was washed with Et2O and then made acidic with conc HCl while cooling in an ice-water bath. The solid was collected, washed with water and dried under high vacuum. There was obtained 10.9 g (53%) of the title compound as a white powder m. p. 137.5°-138°.
Reaction SMILES: CC(C)=O.[OH-:5].[Na+].Br[CH2:8][C:9](=O)[C:10]([CH3:22])([CH3:21])[CH:11](Cl)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[OH2:24]>>[CH3:21][C:10]1([CH3:22])[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]1[C:8]([OH:24])=[O:5]
Reactant: O
Reactant: COc1ccc(C(Cl)C(C)(C)C(=O)CBr)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(C2C(C(=O)O)C2(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69 %

Procedure:
100 ml of acetone are added to a solution of 35.3 g (0.882 mol) of sodium hydroxide in 317 ml of water. Then, at 25° C., 26.5 g (0.083 mol) of 4-bromo-2,2-dimethyl-1-chloro-1-(4-methoxyphenyl)-3-butanone are added dropwise. The mixture is stirred at 25° C. for a further 12 hours, poured onto water and extracted with methylene chloride. The aqueous phase is acidified and extracted again. 12.6 g (69% of theory) of 2,2-dimethyl-3-(4-methoxyphenyl)cyclopropanecarboxylic acid of melting point 115° C. are obtained.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1(=O)[O:19][C:17](=O)[CH2:16][CH2:15]1.O.[NH2:22][NH2:23]>>[CH:8]1([O:7][C:1]2[CH:2]=[CH:3][C:4]([C:14]3[CH2:15][CH2:16][C:17](=[O:19])[NH:22][N:23]=3)=[CH:5][CH:6]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: NN
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: O=C1CCC(=O)O1
Solvent: O
Product: O=C1CCC(c2ccc(OC3CCCCC3)cc2)=NN1

Procedure:
Similarly prepared by reaction of the appropriate phenyl ether with succinic anhydride followed by treatment with hydrazine hydrate were:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:24][O:23][N:22]([CH3:21])[C:17]([CH:14]1[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15]1)=[O:19]
Reactant: CNOC
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
A mixture of 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (10 g, 38.0 mmol), N,O-dimethylhydroxylamine hydrochloride (5.56 g, 57.0 mmol), and CH2Cl2 (120 mL) was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.92 g, 57.0 mmol) and 4-(dimethylamino)pyridine (0.464 g, 3.80 mmol). The mixture was cooled in an ice bath and treated with N,N-diisopropylethylamine (13.23 mL, 76 mmol) over 3 min. After 10 min, the cooling bath was removed and the mixture was stirred at RT overnight (˜14 h). The mixture was diluted with CH2Cl2 (150 mL), washed with saturated NaHCO3 (3×50 mL), 2 M HCl (2×50 mL) and brine, dried over MgSO4, and concentrated to provide a residue. The residue was purified by flash chromatography using a 120 g silica gel cartridge and 10:1 Hex/EtOAc to elute the product. The fractions containing the product were pooled and concentrated on a rotary evaporator to give the title compound (7.8 g, 25.5 mmol, 67% yield) as a pale yellow oil. LC-MS: 307.1, (M+H)+. 1H-NMR (400 MHz, CDCl3) δ ppm 7.25-7.37 (5H, m), 5.11 (2H, s), 4.21 (2H, s), 3.66-3.71 (3H, m), 3.16 (3H, s), 2.83 (3H, d, J=5.93 Hz), 1.64-1.75 (4H, m).