Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5](/[CH:9]=[CH:10]/[S:11]([NH2:14])(=[O:13])=[O:12])[CH:4]=1.[Cl:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].O>O1CCOCC1>[Cl:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([NH:14][S:11](/[CH:10]=[CH:9]/[C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)(=[O:12])=[O:13])=[O:19]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: NS(=O)(=O)/C=C/c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NS(=O)(=O)/C=C/c1cccnc1)c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (36 mg, 0.9 mmol) was added to a solution of (E)-2-Pyridin-3-yl-ethenesulfonic acid amide (56 mg, 0.3 mmol) in dioxane (1 mL) and the mixture was shaken for 30 minutes. A solution of 2,4-dichlorobenzoyl chloride (63 μL, 0.45 mmol) in dioxane (0.5 mL) was added to the mixture and the whole was shaken at room temperature for 18 hours. Water (0.1 mL) was added to the mixture and the whole was concentrated in vacuo. The resultant residue was purified by preparative HPLC to give (E)-2-pyridin-3-yl-ethenesulfonic acid 2,4-dichloro-benzoylamide (29.1 mg, 26%) as sodium salt.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH:17]=O.[BH3-]C#N.[Na+]>CO>[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][NH:11][C:10]1[CH:9]=[CH:8][NH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: O=Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1[nH]ccc1NCc1ncc[nH]1
Yield: 98.5 %

Procedure:
A reaction mixture with 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.2 g, 1.30 mmol), 2-imidazolecarboxaldehyde (0.15 g, 1.53 mmol), NaCNBH3 (0.082 g, 1.30 mmol) and OHAc (0.15 mL, 2.60 mmol) in methanol (5 mL) was stirred at r.t. for 2 h. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate. Washed with water and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and concentrated. The crude product was purified by flash column chromatography (CH2Cl2/methanol gradient; 0 to 20% methanol), obtaining 0.30 g (99%) of the title compound.
Reaction SMILES: [CH:1]1([CH:6]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:7]2[O:8][C:9]3[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.O1CCCC1.[OH-].[Na+]>[CH:1]1([CH:6]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:7]2[O:8][C:9]3[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3c(F)cc(F)cc3c2C)C2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCC2)oc2c(F)cc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
Ethyl 3-{[(4-{[cyclopentyl(5,7-difluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (240 mg) synthesized in Example A207 was dissolved in ethanol (1.0 mL)-tetrahydrofuran (1.0 mL), 1N aqueous sodium hydroxide solution (0.96 mL) was added to the solution, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (4 mL) was added to the residue, and the mixture was neutralized with 1N hydrochloric acid (0.96 mL) under ice-cooling, and stirred for 15 min. The resulting precipitate was collected by filtration, and dried to give the title compound (185 mg, 82%) as a colorless amorphous form.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([O:27][CH3:28])[C:15]=1[C:16](O)=[O:17])[CH3:13]>>[CH2:12]([C:14]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([O:27][CH3:28])[C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17])[CH3:13]
Reactant: CCc1cc(C(F)(F)F)cc(OC)c1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: CCc1cc(C(F)(F)F)cc(OC)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, light yellow oil, MS: m/e=385.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-ethyl-6-methoxy-4-trifluoromethyl-benzoic acid (intermediate AR).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([OH:33])=O)=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:37][CH2:36]4)=[O:33])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[C:14]=23)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2nccc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: Cc1c(C(=O)N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c2nccc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c2) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9](O)=O)=[CH:5][NH:4][C:3]1=[O:12].[ClH:13]>>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH2:9][Cl:13])=[CH:5][NH:4][C:3]1=[O:12]
Reactant: Cl
Reactant: Cn1c(=O)[nH]cc(C(=O)O)c1=O
Product: Cn1c(=O)[nH]cc(CCl)c1=O
Yield: 52 %

Procedure:
3-methyluracil-5-carboxylic acid was treated with HCl and CH2 using standard chloromethylation conditions to give 3-methyl-5-chloromethyl uracil in 52% yield (following standard work-up and recrystallization from ethyl acetate). NMR (DMSO-6): chemical shifts, peak integrations & D2O exchange experiments diagnostic for structure.
Reaction SMILES: [CH2:1]([CH:4]([C:19]([O:21]C1C(Cl)=C(Cl)C(Cl)=C(Cl)C=1Cl)=O)[C:5]([O:7]C1C(Cl)=C(Cl)C(Cl)=C(Cl)C=1Cl)=O)[CH:2]=[CH2:3].C(N(CC)CC)C.[NH2:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][N:42]=1>CC(C)=O>[CH2:1]([C:4]1[C:5](=[O:7])[N:42]2[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:41]2=[N:40][C:19]=1[OH:21])[CH:2]=[CH2:3]
Reactant: C=CCC(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: COc1ccnc(N)c1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C=CCc1c(O)nc2cc(OC)ccn2c1=O
Reaction time: 16 h
Yield: 64.8 %

Procedure:
Bis(pentachlorophenyl) allylmalonate (905 mg, 1.412 mmol) and triethylamine (0.359 ml, 2.58 mmol) were added to a slurry of 2-amino-4-methoxypyridine (160 mg, 1.289 mmol) in acetone (6.5 ml). The slurry was stirred for 16 hours, filtered, and washed with acetone to yield the title compound as a white solid (194 mg, 65%). LCMS (ES+) m/z 233.0 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([CH2:7]Br)=[CH:5][CH:4]=[C:3]([C:9]#[N:10])[CH:2]=1.[CH3:11][NH2:12]>C(#N)C>[CH3:11][NH:12][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:9]#[N:10])=[CH:2][CH:1]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CN
Solvent: CC#N
Product: CNCc1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
A solution of a-bromo-p-tolunitrile (4.90 g, 25 mmol) in acetonitrile (50 mL) was added dropwise to a stirring solution of 40% aqueous methylamine (21.5 mL, 250 mmol) in acetonitrile (50 mL) at 0° C. The reaction mixture was stirred 0.5 h, then concentrated in vacua. Water was added to the residue and extracted 2× with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacua to give 1.41 g of 4-(methylaminomethyl)benzonitrile as a yellow oil containing ~30% of N,N-bis(4-benzonitrile)methyl-amine. The aqueous was adjusted to pH>8 and extracted 2× with 9:1 dichloromethane:methanol. The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacua to give 1.13 g of pure 4-(methylamino)benzonitrile as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C@@H:8]([OH:10])[CH3:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:33]1[C:34]([N+:39]([O-:41])=[O:40])=[N:35][CH:36]=[CH:37][CH:38]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(=O)=O.C1(C)C=CC=CC=1.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C@H:8]([O:10][C:33]2[C:34]([N+:39]([O-:41])=[O:40])=[N:35][CH:36]=[CH:37][CH:38]=2)[CH3:9])[CH:7]=1
Reactant: COc1ccc(F)cc1[C@H](C)O
Reactant: O=[N+]([O-])c1ncccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1[C@@H](C)Oc1cccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To an ice cooled solution (0° C.) of (S)-1-(5-fluoro-2-methoxy-phenyl)-ethanol (see H. C. Brown, Tet. Letts., 35 (14), 2141-4, 1994. Optical purity of alcohol: >99.5% e.e. (based on SFC on a chiral column: Chiralpak IA (250*4.6 mm i.d.), eluent 5% methanol alcohol in carbon dioxide, Flow rate 4 mL/min, temp. 40° C., back pressure 150 bar, Rt=2.16 min (opposite enantiomer Rt=2.35 min))) (2.00 g, 11.7 mmol), triphenylphosphine (3.54 g, 13.5 mmol, 1.15 eq.) and 3-hydroxy-2-nitro-pyridine (1.81 g, 12.9 mmol, 1.1 eq) in toluene (100 mL) was added a solution of diisopropyl azodicarboxylate (2.73 g, 13.5 mmol, 1.15 eq.) in toluene (20 mL) at such a rate as to maintain the temperature below 10° C. The resulting mixture was stirred at room temperature for 18 hr. The crude reaction mixture was extracted with aqueous potassium hydroxide solution (2M, 2×50 mL). The organic phase was washed with brine and dried over magnesium sulphate before filtering. The filtrate was evaporated under reduced pressure to give an orange semi solid material. This material was suspended in diethyl ether and heptane (80:20 by volume) and filtered. This filtrate was evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a gradient of diethyl ether in heptane (50:50 to 80:20 by volume) to produce the title compound as a pale yellow oil (3.48 g, 86%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([S:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([NH:20][C:21]([NH2:23])=[O:22])=[C:17]([CH:19]=2)[NH2:18])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:26][O:27][C:28]([NH:30][C:31](=[N:34][C:35]([O:37][CH3:38])=[O:36])SC)=[O:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C.CO>[CH3:38][O:37][C:35]([NH:34][C:31]([NH:30][C:28]([O:27][CH3:26])=[O:29])=[N:18][C:17]1[CH:19]=[C:13]([O:12][S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=2)(=[O:11])=[O:10])[CH:14]=[CH:15][C:16]=1[NH:20][C:21]([NH2:23])=[O:22])=[O:36]
Reactant: NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)NC(=Nc1cc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)ccc1NC(N)=O)NC(=O)OC

Procedure:
12.5 g of 5-(3-trifluoromethylphenylsulfonyloxy)-2-ureidoaniline, 13.6 g of N,N'-bismethoxycarbonyl-S-methylisothiourea and 100 mg of p-toluenesulfonic acid in 90 ml of ethyl acetate and 45 ml of methanol are stirred under reflux for 20 minutes. After cooling down, the mixture is evaporated to dryness under reduced pressure, and the residue is stirred with diisopropyl ether and filtered off with suction. Recrystallization from ethyl acetate/diisopropyl ether, melting point 131° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C@@H:6]1[C@@H:13]([OH:14])[C@H:12]([CH3:15])[O:11][C@@H:8]([O:9]C)[CH2:7]1)=[O:4].[N+](=[CH2:20])=[N-].B(F)(F)F>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:20][O:14][C@H:13]1[C@H:12]([CH3:15])[O:11][CH:8]([OH:9])[CH2:7][C@@H:6]1[NH:5][C:3](=[O:4])[C:2]([F:17])([F:16])[F:1]
Reactant: CO[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@@H](O)[C@H](C)O1
Reactant: C=[N+]=[N-]
Agent: FB(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CO[C@@H]1[C@@H](NC(=O)C(F)(F)F)CC(O)O[C@H]1C
Yield: 98 %

Procedure:
Treatment of 2.57 g; 10 mmoles of methyl 2,3,6-trideoxy-3-trifluoroacetamido-α-L-arabino-hexopyranoside (III-A) in methylene dichloride with diazomethane/boron-trifluoride, as described in Example I gave the corresponding 4-O-methylderivative (III-B, 1.7 g., 63%): m.p. 185°; [α]D23° =-101° (c=1, in CHCl3); mass spectrum m/e 271 (H+); pmr spectrum (CDCl3); 1.31 (d, CH3 --C--5), 3.30 and 3.43 (two s, OCH3) and 4.70δ (broad s, C--1--H). Acid hydrolysis of compound III-B as in Example I (1.63 g., 6 mmoles) gave 2,3,6-trideoxy-4-O-methyl-3-trifluoroacetamido-L-arabino-hexopyranose (III-C, 1.51 g., 98%): m.p. 201°; [α]D23° =-12.7° (c=0.48, in CHCl3); mass spectrum m/e 257 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].Cl>CO.O>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[C:21]([OH:20])[CH:22]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nc1cccc(O)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (0.028 g, 0.1 mmol) in MeOH:H2O (1.8:0.2 mL) was added 3-hydroxyaniline (0.033 g, 0.3 mmol) and heated in a sealed tube at 100° C. for 24 h. The resulting reaction was diluted with H2O (10 mL), acidified with 2N HCl (pH>2), saturated and the resulting solid was filtered to give the desired product, N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl))-2,4-pyrimidinediamine (R926210). Purification can be done by filtration through a pad of silica gel using 1-5% MeOH in CH2Cl2 or by crystallization using an appropriate solvent system. 1H NMR (CDCl3+CD3OD): δ 7.76 (bs, 1H), 7.30 (d, 1H, J=2.4 Hz), 7.10 (m, 1H), 7.03 (t, 1H, J=8.1 Hz), 6.89 (dd, 2H, J=2.4 and 9 Hz), 6.78 (d, 1H, J=8.7 Hz), 6.42 (dd, 1H, J=2.4 and 9 Hz), 4.22 (m, 4H); 19F NMR (CDCl3+CD3OD): −47196; LCMS: ret. time: 19.55 min.; purity: 95%; MS (m/e): 355 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[BH4-].[Na+].[C:37](O)(=O)[CH3:38]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([N:21]([CH2:37][CH3:38])[CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCN(c2ccncc2)CC1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCN(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(Method B) 4-(6-Chloronaphthalene-2-sulfonyl)-1-[1-(4-pyridyl)-4-piperidinylamino]-2-piperazinone (14 g) was dissolved in acetic acid (160 ml) and the reaction mixture was treated portionwise with sodium borohydride (11.36 g) while keeping the temperature at 20° C., and then stirred at room temperature for 15 hours. The reaction mixture was concentrated and the residue was made alkaline by adding an aqueous solution of sodium hydroxide, extracted with dichloromethane, dried and concentrated. The residue obtained was crystallized from ethanol to obtain the title compound (12.96 g) as colorless crystals.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:15]([O-])(=[O:18])[C:16]#[CH:17].[Na+].S(Cl)(Cl)=O.[C:25]([Cl:29])(=[O:28])[C:26]#[CH:27]>C1C=CC=CC=1>[C:25]([Cl:29])(=[O:28])[C:26]#[CH:27].[C:15]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:18])[C:16]#[CH:17]
Reactant: C#CC(=O)[O-]
Reactant: OCCCCCc1ccccc1
Agent: C#CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: C#CC(=O)OCCCCCc1ccccc1

Procedure:
With stirring, 1 gram of 5-phenylpentanol was added dropwise to a mixture of 0.25 g of sodium hydride (60% oil suspension) and 25 ml of dried benzene. The mixed solution is further stirred at ambient temperatures for one hour. A benzene solution of propiolic acid chloride is prepared by stirring a mixture of 0.62 g of sodium propiolate, 0.80 g of thionyl chloride, and 20 ml of dried benzene at ambient temperatures for five hours. The benzene solution of propiolic acid chloride thus prepared is added to the mixed solution, stirred at ambient temperatures for five hours, and refluxed for one hour. After the reaction is completed, the reaction solution is washed successively with water and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue is subjected to silicagel column chromatography to yield 5-phenylpentyl propiolate (compound 1).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][CH:9]([O:16][CH3:17])[CH:10]([CH3:15])/[C:11](/[F:14])=[CH:12]\[OH:13]>[O-2].[O-2].[O-2].[Cr+6].C(Cl)Cl>[CH3:7][O:8][CH:9]([O:16][CH3:17])/[C:10](/[CH3:15])=[C:11](/[F:14])\[CH:12]=[O:13]
Reactant: COC(OC)C(C)/C(F)=C\O
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(OC)/C(C)=C(/F)C=O
Reaction time: 2 h

Procedure:
Chromium trioxide (145 g., 1.45 mol) was added to 5 l. of methylene chloride in a 12 l. round bottomed flask fitted with argon inlet and mechanical stirrer. Pyridine (230 ml., 2.9 mol) was added and the mixture was stirred for 2 hours. Celite (290 g.) was added and then E-4,4-dimethoxy-2-fluoro-3-methyl-buten-1-ol was added in one portion and stirred for 30 minutes. The mixture was filtered, evaporated at 30° C. to ~5% of its volume and diluted with 500 ml. of ether. This mixture was filtered and evaporated to ~100 ml. at 30° C. The resulting E-4,4-dimethoxy-2-fluoro-3-methyl-buten-1-al was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[O:32]=[C:33]1[NH:37][CH:36]([CH2:38][C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH2:35][O:34]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:43][C:42]3[CH:41]=[CH:40][C:39]([CH2:38][CH:36]4[CH2:35][O:34][C:33](=[O:32])[NH:37]4)=[CH:45][CH:44]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Nc1ccc(CC2COC(=O)N2)cc1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CC3COC(=O)N3)cc2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 4-[(2-oxo-1,3-oxazolidin-4-yl)methyl]aniline (Specs, 130 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.OS(O)(=O)=O.[N+:24]([O-])([OH:26])=[O:25]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[O:9])=[CH:6][C:7]=1[N+:24]([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: O=C(c1ccc(Br)cc1)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Product: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(Br)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
The crude (4-Bromo-phenyl)-(4-nitro-phenyl)-methanone (15 g, 49 mmol) was dissolved in 45 mL of dichloroethane and added dropwise via addition funnel to a mixture of concentrated H2SO4(aq) (21 mL, 392 mmol) and fuming HNO3(aq) (15.7 mL, 392 mmol). The mixture was stirred at 60° C. overnight. Subsequently the mixture was poured over ice water and allowed to stir resulting in precipitation of the product. The product was filtered and dried affording 78% yield of the desired (4-Bromo-3-nitro-phenyl)-(-4-nitro-phenyl)-methanone (13.1 g, 38 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Cl:10][SiH:11]([Cl:13])[Cl:12]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[C:2]1([CH3:1])[CH:9]=[CH:8][C:5]([CH2:6][CH2:7][Si:11]([Cl:13])([Cl:12])[Cl:10])=[CH:4][CH:3]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: C=Cc1ccc(C)cc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: Cc1ccc(CC[Si](Cl)(Cl)Cl)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
Into a 3 liter round-bottom flask fitted with a reflux condenser, addition funnel and magnetic stir bar, was charged 4-methylstyrene (904.4 g, 7.65 mols), VCAT (2.25 g, 50 ppm) and phenothiazine (1.94 g, 1000 ppm). The reaction mixture was heated to 70° C. and then trichlorosilane (1036.6 g, 7.65 mols) was added dropwise to the reaction mixture. During the addition, the reaction mixture was maintained between 80 to 100° C. After the addition was finished, the reaction mixture was kept at 70° C. for additional two hours. After distillation, >98% pure (2-p-tolyl-ethyl)trichlorosilane (1565 g, 6.19 mols) was obtained (collected at 75° C./1 mmHg). The product structure was characterized by GC-MS.
Reaction SMILES: [CH3:1][C@@H:2]1[C@:25]2([O:31][CH2:30][C@H:28]([CH3:29])[CH2:27][CH2:26]2)[O:24][C@H:4]2[CH:5]=[C:6]3[C@@:20]([CH3:21])([C@@H:3]12)[C:19](=[O:22])[CH2:18][C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C:12](=[O:23])[CH2:11]2.[Br-:32].[NH+]1C=CC=CC=1.O>O1CCCC1>[Br:32][CH:13]1[CH2:14][C@@:15]2([CH3:16])[C@@H:10]([CH2:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][C:19](=[O:22])[C@@:20]2([CH3:21])[C:6]3=[CH:5][C@@H:4]3[O:24][C@@:25]4([O:31][CH2:30][C@H:28]([CH3:29])[CH2:27][CH2:26]4)[C@@H:2]([CH3:1])[C@@H:3]32)[CH2:11][C:12]1=[O:23]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C=C3[C@@H]4CC[C@H]5CC(=O)CC[C@]5(C)[C@H]4CC(=O)[C@]3(C)[C@H]1[C@@H]2C
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C=C3[C@@H]4CC[C@H]5CC(=O)C(Br)C[C@]5(C)[C@H]4CC(=O)[C@]3(C)[C@H]1[C@@H]2C
Temperature: 25 °C

Procedure:
500 mg of (25R)-5a-spirost-14-ene-3,12-dione is dissolved in 15 ml of tetrahydrofuran and mixed with 453 mg (1.1 eq) of pyridinium bromide-perbromide, dissolved in 25 ml of tetrahydrofuran. After two and one half hours of stirring at room temperature, the reaction is arrested by adding 20 ml of water and the mixture is extracted with dichloromethane. The organic phase is washed with sodium chloride solution, dried on magnesium sulfate, the solvent is removed and the residue is chromatographed with petroleum ether/ethyl acetate (4:1) on silica gel. The combined fractions are concentrated by evaporation and stirred overnight in 10 ml of methanol. After filtration and evaporation of the solvent, there is obtained: