Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]([NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([NH:23][C@@H:24]([C@H:29]([OH:31])C)[C:25]([O:27][CH3:28])=[O:26])=[O:22])=[O:15])=[O:8])(=[O:3])[CH3:2].[CH3:43]N1CCOCC1.OC[C@H](NC([C@@H]1CCCN1)=O)C(OC)=O>C(Cl)Cl.CN(C=O)C>[C:1]([O:4][C@@H:5]([CH3:43])[C@@H:6]([NH:32][C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([NH:23][C@@H:24]([CH2:29][OH:31])[C:25]([O:27][CH3:28])=[O:26])=[O:22])=[O:15])=[O:8])(=[O:3])[CH3:2]
Reactant: CN1CCOCC1
Reactant: COC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](COC(C)=O)NC(=O)OCc1ccccc1)[C@@H](C)O
Agent: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](NC(=O)OCc1ccccc1)[C@H](C)OC(C)=O
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
(2S)-1-((2R)-3-acetoxy-2-(benzyloxycarbonylamino)-butanoyl)-pyrrolidine-2-carboxylic acid (5) (1.3 g, 2.62 mmol) was dissolved in CH2Cl2 (15 mL), NMM (0.43 mL) and IBCF (0.51 mL) was added at −10° C. and stirred for 30 minutes under inert atmosphere. A mixture of(S)-methyl-3-hydroxy-2-((S)-pyrrolidine-2-carboxamido)-propionate (4) (992 mg, 3.93 mmol) and NMM (0.43 mL) in DMF (5 mL) were added drop wise to the reaction mixture and stirring was continued for another 3 h at RT. The reaction mixture was diluted with DCM (200 mL), washed with water (20 mL), citric acid solution (2×20 mL) and brine (2×50 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude material was purified by silica gel column chromatography eluting with 5% CH3OH/CH2Cl2 to afford compound 6 (270 mg, 17.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([OH:7])=O.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[O:7])[CH:8]=[C:9]([I:11])[CH:10]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc(Br)cc(I)c1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2cc(Br)cc(I)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
A solution of 3-bromo-5-iodo-benzoic acid (5.0 g, 15.3 mmol) in 100 mL of thionyl chloride was heated under reflux for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting solid was then dissolved in 100 mL of CH2Cl2. N-Methyl-piperazine (2.5 mL, 22.9 mmol) and DIPEA (5.3 mL, 30.6 mmol) were added and the reaction mixture was stirred at room temperature for 3 h. The resulting solution was concentrated under reduced pressure and the crude material was purified by column chromatography (Isco™ 330 g) using 20% MeOH/EtOAc as eluting solvent to afford 5 g (80%) of (3-bromo-5-iodo-phenyl)-(4-methyl-piperazin-1-yl)-methanone as a white solid.
Reaction SMILES: [N:1]([CH:4]1[CH2:21][CH2:20][C:7]2=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:9][C:10]([S:11][CH:12]([CH3:14])[CH3:13])=[C:6]2[C:5]1=[O:22])=[N+]=[N-].[C:23](OC(=O)C)(=[O:25])[CH3:24]>[C].[Pd].C(O)(=O)C>[C:23]([NH:1][CH:4]1[CH2:21][CH2:20][C:7]2=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:9][C:10]([S:11][CH:12]([CH3:14])[CH3:13])=[C:6]2[C:5]1=[O:22])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1sc(SC(C)C)c2c1CCC(N=[N+]=[N-])C2=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(SC(C)C)c2c1CCC(NC(C)=O)C2=O
Yield: 77.8 %

Procedure:
A mixture of ethyl 5-azido-4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (1.60 g), palladium-carbon (5%, 50% wet, 1.6 g), acetic acid (30 ml) and acetic anhydride (15 ml) was subjected to a catalytic reduction reaction at room temperature under 1 atm. The insoluble substances were filtered off; the filtrate was poured over water and extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried (MgSO4), after which the solvent was distilled off to yield ethyl 5-acetylamino-4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (1.30 g, 77.8%), which was then recrystallized from ethyl acetate-hexane. Colorless prisms. Melting point 170-171° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CO[CH:17](OC)[CH2:18][Br:19].N>S(=O)(=O)(O)O>[Br:19][CH2:18][CH:17]1[NH:1][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: COC(CBr)OC
Reactant: Nc1ncccc1Cc1ccccc1
Agent: N
Agent: O=S(=O)(O)O
Product: BrCC1Nc2ncccc2Cc2ccccc21
Reaction time: 1 h
Yield: 74.5 %

Procedure:
A mixture of 2-amino-3-benzylpyridine (12.0 g, 65.2 mmol) and bromoacetaldehyde dimethyl acetal (19 g, 112.4 mmol, 1.7 eq.) in a 250 ml round-bottomed flask was treated at room temperature with concentrated sulphuric acid (50 ml) by quick addition. A vigorous exothermic reaction took place. After stirring for one hour the dark mixture was poured on ice (ca. 500 ml). Concentrated ammonia was added to basify the mixture. Extraction was done with ethyl acetate (100 ml) and dichloromethane (2×150 ml). The combined organic layers were dried with Na2SO4. Evaporation under vacuum gave 10-bromomethyl-10,11-dihydro-5H-benzo[e]pyrido[2,3-b]azepine as a brown powder (14 g, 48.6 mmol) in 75% yield. Mass analysis: M+1 289,291 (Br-isotope) major peak.
Reaction SMILES: C([O-])(=O)C.[CH:5]1([C:8]2[N:9](C(OCC(C)C)=O)[C:10]3[C:11]([N:27]=2)=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]4[O:25][CH2:24][CH2:23][NH:22][CH2:21][C:20]=4[CH:26]=2)[CH:15]=3)[CH2:7][CH2:6]1.Cl[C:36]1[C:45]2[CH2:44][C:43]([CH3:47])([CH3:46])[CH2:42][CH2:41][C:40]=2[N:39]=[C:38]([CH2:48][N:49]([CH3:51])[CH3:50])[N:37]=1>>[CH:5]1([C:8]2[NH:9][C:10]3[C:11]([N:27]=2)=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]4[O:25][CH2:24][CH2:23][N:22]([C:36]5[C:45]6[CH2:44][C:43]([CH3:46])([CH3:47])[CH2:42][CH2:41][C:40]=6[N:39]=[C:38]([CH2:48][N:49]([CH3:51])[CH3:50])[N:37]=5)[CH2:21][C:20]=4[CH:26]=2)[CH:15]=3)[CH2:7][CH2:6]1
Reactant: CC(C)COC(=O)n1c(C2CC2)nc2ncc(-c3ccc4c(c3)CNCCO4)cc21
Reactant: CN(C)Cc1nc(Cl)c2c(n1)CCC(C)(C)C2
Agent: CC(=O)[O-]
Product: CN(C)Cc1nc2c(c(N3CCOc4ccc(-c5cnc6nc(C7CC7)[nH]c6c5)cc4C3)n1)CC(C)(C)CC2

Procedure:
Prepared as acetate according to the method of example 6 by using 2-methylpropyl 2-cyclopropyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate (reagent preparation 19) in step 1 and 1-(4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)-N,N-dimethylmethanamine (reagent preparation 17) in step 3. 1H NMR (400 MHz, d6-DMSO): 8.49 (s, 1H), 7.98 (s, 1H), 7.68 (d, 1H), 7.51 (dd, 1H), 7.01 (d, 1H), 4.63 (s, 2H), 4.30 (m, 2H), 3.85 (m, 2H), 2.68 (m, 2H), 2.44 (s, 2H), 2.14 (m, 1H), 2.10 (s, 6H), 1.88 (s, 2H), 1.59 (m, 2H), 1.10 (m, 4H), 0.85 (s, 6H). MS (EI) for C31H37N7O: 524 (MH+).
Reaction SMILES: [CH2:1]([C:14]1[C:15]2[S:24][C:23](CC)=[C:22]([Br:27])[C:16]=2[S:17][C:18]=1[C:19]([O-:21])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C1COCC1.[Li+].[OH-].Cl>O.CO>[CH2:1]([C:14]1[C:15]2[S:24][CH:23]=[C:22]([Br:27])[C:16]=2[S:17][C:18]=1[C:19]([OH:21])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCc1c(C(=O)[O-])sc2c(Br)c(CC)sc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCc1c(C(=O)O)sc2c(Br)csc12

Procedure:
3-Tridecyl-6-bromo-thieno[3,2-b]thiophene-2-carboxylic acid (154) was prepared using the following procedure. Compound 153 (71.0 g, 0.15 mol) was dissolved into a mixture of THF (400 mL), methanol (50 mL), and LiOH (72 mL, 10% solution). This mixture was refluxed overnight and poured into concentrated hydrochloric acid (300 mL). The acid mixture was then diluted to 1000 mL with water. Solid was filtrated and washed with water (3×500 mL). The light yellow solid was washed with methanol (300 mL) and dried under vacuum overnight (46.40 g. 69.5%). Mp: 88-90° C. 1H NMR (300 MHz, CD2Cl2) δ 7.55 (s, 1H), 3.17 (t, 2H), 1.75 (t, 2H), 1.26 (m, 20H), 0.87 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[OH-].[K+].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH2:16]([O:15][C:13]([CH2:12][N:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]1=[O:8])=[O:14])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: O=c1ncc(Cl)c[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)Cn1cc(Cl)cnc1=O
Yield: 39 %

Procedure:
5-Chloropyrimid-2-one (0.02 mol) was added to a stirred solution of KOH (0.02 mol) in ethanol (100 ml) followed by addition of ethyl bromoacetate (0.023 mol). The reaction mixture was heated under reflux for 4 h. The reaction mixture was then evaporated to dryness at reduced pressure and the residue was extracted with chloroform (150 ml). The chloroform extract, after filtration, was washed with aqueous 0.5 N NaOH (2×3 ml) and water (3 ml). Evaporation of the dried (MgSO4) solution left the product which was recrystallized from acetone; yield 39%, m.p. 175°-177° C. (Found: C 44.65; H, 4.17. Calc. for C8H9ClN2O3 : C 44.36; H, 4.19).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12](S)=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[CH3:17][NH:18][NH2:19]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12]([N:18]([CH3:17])[NH2:19])=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2nnc(S)cc2C1
Reactant: CNN
Product: CCOC(=O)N1CCc2nnc(N(C)N)cc2C1

Procedure:
A solution of 4.8 g of 5,6,7,8-tetrahydro-3-mercapto-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester in 20 cc of methylhydrazine is stirred at a bath temperature of 100° for 1 hour. The reaction solution is cooled with ice, and the precipitated reaction product is filtered off. The title compound has a M.P. of 121°-123° (decomp., from dimethoxyethane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.Br.[N+:27]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][NH:33][CH2:34]2)([O-:29])=[O:28].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:27]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][N:33]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:34]2)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cccc2c1CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(N3Cc4cccc([N+](=O)[O-])c4C3)c(F)cc2c1=O
Yield: 15.7 %

Procedure:
213 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 176 mg of 4-nitroisoindoline hydrobromide, 164 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 47 mg of the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[C:11]([F:17])[CH:10]=2)[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22].[C:23](=O)([O-])[O-].[K+].[K+].COP(C(=[N+]=[N-])C(=O)C)(=O)OC>CO>[NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[CH:23])=[C:11]([F:17])[CH:10]=2)[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1nc(-c2ccc(C=O)c(F)c2)c(C)c(N)c1Cl
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-c2nc(C(=O)OC)c(Cl)c(N)c2C)cc1F
Yield: 69.9 %

Procedure:
To a solution of methyl 4-amino-3-chloro-6-(3-fluoro-4-formylphenyl)-5-methylpicolinate (358 mg, 1.1 mmol) and potassium carbonate (537 mg, 3.9 mmol) in methanol (11 mL) at room temperature was added 1 mL of dimethyl(1-diazo-2-oxopropyl)phosphonate (Bestmann-Ohira reagent, crude reagent) for 3 h. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were dried organics over anhydrous sodium sulfate, filtered, and adsorbed onto silica gel. Purification by flash chromatography (0-50% ethyl acetate/hexanes) provided the title compound as a yellow solid (245 mg, 69%).
Reaction SMILES: [CH3:1][Mg]Br.[NH2:4][C:5]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].O>CCOCC>[NH2:4][C:5]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:6]=1[C:7]([CH3:1])([OH:8])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: C[Mg]Br
Solvent: O
Solvent: CCOCC
Product: CC(O)(c1ccccc1)c1cc(Cl)ccc1N
Reaction time: 8 h
Yield: 75 %

Procedure:
Methylmagnesium bromide (267 ml of 3M ether-solution; 0.8 mole) is added during 45 minutes to a solution of 2-amino-5-chlorobenzophenone (46.3 g; 0.2 mole) in 1 liter of ether. The mixture is refluxed for 5 hours and allowed to stand overnight. It is then cooled in ice and decomposed with 400 ml of water. The ether layer is decanted, washed with saturated salt solution dried (MgSO4) and evaporated. The residue is crystallized from ether-Skellysolve B to give 37.1 g (75% yield), mp 93°-94° C., unchanged on recrystallization. Spectral data support the product structure.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.C1(CC2C=CC=CC=2)C=CC=CC=1.[CH2:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1C=CC=CC=1>[CH2:1]([C:35]1[C:34]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[C:33]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:38]=[CH:37][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: c1ccc(Cc2ccccc2Cc2ccccc2)cc1
Agent: FB(F)F
Solvent: c1ccc(Cc2ccccc2)cc1
Solvent: c1ccccc1
Product: c1ccc(Cc2cccc(Cc3ccccc3)c2Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 9 h

Procedure:
Two thousand one hundred and eighty (2,180) grams (2,060 cc) of benzyl alcohol and 1,560 g (1,780 cc) of benzene were introduced into a 10-liter flask, and 940 g of boron trifluoride gas was blown into the flask. The whole mass was transferred into an autoclave, agitated at 60° C. for 9 hours, heated, thereafter cooled and then separated into the lower layer (acid layer) and upper layer (oil layer). The upper layer (oil layer) was incorporated with 1.5 l of a 10% aqueous solution of sodium hydroxide, repeatedly agitated and washed eight times and then distilled to obtain 480 g of a distillate boiling in the range of 173°-176° C. at 72 mm Hg. This distillate had a boiling point of 261° C. at atmospheric pressure, 175° C. at 72 mm Hg, 149° C. at 29 mm Hg or 85° C. at 1 mm Hg, a specific gravity (30/4° C.) of 0.997, a viscosity of 0.01564 g/cm.sec (59° C.) ad a refractive index (nD25) of 1.570, and it was found to be diphenylmethane as the main ingredient from its NMR spectra and gas chromatography. The yield of the diphenylmethane was about 15% (about 460 g), and other distillates having a high boiling point such as dibenzylbenzene and tribenzylbenzene were produced in an amount of 989 g as by-products.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[N:10]=[CH:11][C:12](N)=[N:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].N([O-])=O.[Na+].[ClH:19]>O.[Cu]Br>[Cl:19][C:12]1[CH:11]=[N:10][C:7]2[CH2:8][CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]=2[N:13]=1
Reactant: CCN1CCc2ncc(N)nc2CC1
Reactant: Cl
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCN1CCc2ncc(Cl)nc2CC1
Temperature: -5 °C
Reaction time: 15 h

Procedure:
26.5 g 7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-ylamine (U.S. Pat. No. 4,409,220) are suspended in 130 ml conc. Hydrochloric acid, combined with 0.1 g copper(I)bromide and cooled to −5° C. A suspension of 11 g sodium nitrite in 14 ml of water is slowly added dropwise. The reaction mixture is stirred for 15 hours at ambient temperature and evaporated almost to dryness. The residue is slowly added to ice water and potassium carbonate. The product is extracted with dichloromethane and precipitated as the hydrochloride with an ethereal HCl solution. 14.3 g product are obtained. M.p=258 262° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26].[N:27]1([CH2:32][C@H:33]2[CH2:37][CH2:36][CH2:35][NH:34]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:34]3[CH2:35][CH2:36][CH2:37][C@@H:33]3[CH2:32][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:14])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[C:20]([Cl:26])=[CH:21][CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: C1CN[C@@H](CN2CCCC2)C1
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1OCc1c(Cl)cccc1Cl
Product: Nc1ncc(-c2ccc(C(=O)N3CCC[C@@H]3CN3CCCC3)cc2)cc1OCc1c(Cl)cccc1Cl

Procedure:
{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl)[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone was prepared from 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid and (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[F:25])(O)O>>[F:25][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:16]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1)[C:20]([OH:22])=[O:21]
Reactant: Oc1ccc2nc(Cl)ccc2c1
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)c(F)c1

Procedure:
Followed Scheme 3: Starting Materials: 2-chloroquinolin-6-ol and 4-borono-3-fluorobenzoic acid. 1H NMR (CD3OD, 400 MHz): δ 8.31 (d, J=8.4 Hz, 1H), 7.94-7.86 (m, 3H), 7.81-7.74 (m, 2H), 7.35 (dd, J=9.2, 2.8 Hz, 1H), 7.15 (d, J=2.8 Hz, 1H). MS (ESI): m/z 283.6 [M+H]+.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]([C:15]1([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CO>[NH:12]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:5]=[C:13]1[C:15]1([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1
Reactant: Nc1cnccc1NC(=O)C1(NC(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(NC1(c2nc3cnccc3[nH]2)CC1)OCc1ccccc1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a medium size microwave vial was added 5 mL of acetic acid and 850 mgs of the crude reaction mixture prepared in the previous step (benzyl 1-(4-aminopyridin-3-lcarbamoyl)cyclopropylcarbamate and benzyl 1-(3-aminopyridin-4-ylcarbamoyl)cyclopropylcarbamate). The vial was sealed and the mixture heated at 120° C. for 70 minutes in the microwave. The vessel was cooled to near 0° C. and 50 mL of cold saturated sodium carbonate was added along with 100 mL of 10:1 DCM/methanol. The product was extracted; the organics washed with brine, dried over magnesium sulfate and evaporated. The product mixture was taken up in 15 mL of methanol and purified using a Shimadzu preparative HPLC employing methanol/water/trifluoroacetic acid where solvent A was 10% methanol/90% water/0.1% trifluoroacetic acid and solvent B was 10% water/90% methanol/0.1% trifluoroacetic acid with a Phenomenex-Luna 10 μm C18 30×100 mm column at a gradient of 0-100% B and a flow rate of 40 mL/min. over 15 minutes with a 10 minute hold. Solvent was removed giving a 70% yield of benzyl 1-(1H-imidazo[4,5-c]pyridin-2-yl)cyclopropylcarbamate as a light yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.44-1.59 (m, 2 H), 1.68-1.83 (m, 2 H), 5.05-5.14 (m, 2 H), 6.99-7.14 (m, 1 H), 7.19-7.41 (m, 4 H), 7.88-7.97 (m, 1 H), 8.40 (d, J=6.5 Hz, 1 H), 8.97 (s, 1H). LCMS rt=1.483 min., m/z 309.2 (M+H), 94.5% purity.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14][CH2:13]4)=[CH:10][CH2:9][C:8]1=[CH:7][C:6](=[O:28])[CH2:5][CH2:4]2.[C:29]([N:33]=[C:34]=[O:35])([CH3:32])([CH3:31])[CH3:30]>CCCCCC>[OH:1][CH2:2][C@@:3]12[C@@H:20]3[C:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([O:21][C:22](=[O:27])[C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:14][CH2:13]4)=[CH:10][CH2:9][C:8]1=[CH:7][C:6](=[O:28])[CH2:5][CH2:4]2.[C:29]([NH:33][C:34](=[O:1])[O-:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N=C=O
Agent: CC(C)(C)C(=O)O[C@H]1CC[C@H]2C3=CCC4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@]12C
Solvent: CCCCCC
Product: CC(C)(C)NC(=O)[O-]

Procedure:
A mixture of 1.5 g. of 19-hydroxy-17β-pivaloxyandrosta-4,7-dien-3-one and 22.5 ml. of t-butylisocyanate was heated at 95°-100° C. under nitrogen for two days, whereupon 45 ml. of hexane was added and the mixture was concentrated. Subsequent filtration yielded 19-hydroxy-17β-pivaloxyandrosta-4,7-dien-3-one N-t-butylcarbamate, mp 163°-167° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29](=[O:33])[CH2:30][CH2:31][CH3:32]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([O:15][CH2:28][C:29](=[O:33])[CH2:30][CH2:31][CH3:32])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: Cc1cn2c3ccc(Br)cc3c3cc(O)cc(c1=O)c32
Reactant: CCCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCC(=O)COc1cc2c(=O)c(C)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
10-bromo-2-hydroxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (250 mg) obtained in Example 49 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (210 mg) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and 1-bromo-2-pentanone (188 mg) was added to the mixture. The mixture was stirred at room temperature for 12 hours, and the reaction mixture was poured into ice water (500 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride containing 2% methanol) to obtain the title compound (150 mg, 48%).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH2:8][O:9]C(=O)C)(=[O:6])[O:4][CH3:5].[Na].C(OC)(=O)C.CO>CO>[CH3:1][O:2][P:3]([CH2:7][CH2:8][OH:9])(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(CCOC(C)=O)OC
Agent: [Na]
Solvent: CO
Solvent: COC(C)=O
Product: COP(=O)(CCO)OC
Yield: 84 %

Procedure:
600 g of 2-acetoxyethane-phosphonic acid dimethyl ester are heated for 5 hours to 65°-75°C in 600 ml of methanol to which 3 g of sodium had been added. A mixture of methyl acetate/methanol is removed continuously by distillation. The reaction being terminated, the residue is submitted to distillation under reduced pressure, 369 g of 2-hydroxyethane-phosphonic acid dimethyl ester (boiling point: 122°C/0.2 torr) are obtained, corresponding to a yield of 84% in the theoretical.