Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Mg].[B:10](OC)([O:13]C)[O:11]C.S(=O)(=O)(O)O>CCOCC>[C:4]1([CH3:8])[CH:5]=[CH:6][CH:7]=[C:2]([B:10]([OH:13])[OH:11])[CH:3]=1
Reactant: COB(OC)OC
Reactant: Cc1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: Cc1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of m-bromotoluene (25 g. 0.146 mol) in ether (200 ml) was added dropwise to magnesium (4.0 g, 0.17 mol) in ether (50 ml) at room temperature over a period of 3 hours under a nitrogen atmosphere. After the addition, the reaction mixture was stirred for 12 hours at room temperature. The Grignard reagent was added slowly to a solution of trimethyl borate (15.6 g, 17 ml, 0.15 mol) in ether (500 ml) over a period of 4hours at -78° C. and stirred for 12 hours at room temperature. The reaction mixture was hydrolyzed with 30% sulfuric acid (50 ml). The ether layer was separated, washed with water (3×250 ml) and dried over Na2SO4. The solvent was removed on a rotary evaporator and the solid obtained was recrystallized from water. M.P. 160°-161° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][C:19]4[N:24]=[C:23]([C:25]([O:27]C)=O)[CH:22]=[CH:21][CH:20]=4)=[O:17])[CH:11]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.O.[NH2:30][NH2:31]>C(O)C>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:25]([NH:30][NH2:31])=[O:27])[N:24]=4)=[O:17])[CH:11]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(NC(=O)c2cc(-c3ccc(C4CC4)nc3)ccn2)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cccc(NC(=O)c2cc(-c3ccc(C4CC4)nc3)ccn2)n1
Reaction time: 4 h
Yield: 47 %

Procedure:
The methyl 6-(6-cyclopropyl-3,4′-bipyridine-2′-carboxamido)picolinate from the previous step were suspended in ethanol (20 mL), hydrazine hydrate (700 μL, 14.4 mmol) was added, and the reaction was heated to relfux for 4 hours. The reaction mixture was concentrated and the resultant solids were suspended in acetronitrile and collected by filtration. The solids were washed with acetonitrile (2×100 mL) and diethyl ether (2×100 mL), and dried under reduced pressure to afford 1.21 g (47% yield) of 6-cyclopropyl-N-(6-(hydrazinecarbonyl)pyridin-2-yl)-3,4′-bipyridine-2′-carboxamide as a white solid.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH:4]([CH2:6][CH3:7])[OH:5].[N:9]#[C:10][NH2:11].[O-]CC.[Na+].O>C(O)C>[NH2:11][C:10]1[O:5][C:4]([CH2:6][CH3:7])=[C:3]([CH2:2][CH3:1])[N:9]=1
Reactant: CCC(=O)C(O)CC
Reactant: N#CN
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1nc(N)oc1CC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 29.7 %

Procedure:
Propioin (1.03 g, 8.87 mmol) was dissolved in ethanol (15 mL). Cyanamide (0.75 g, 17.7 mmol) and sodium ethoxide (1.21 g, 17.7 mmol) were added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (dichloromethane:methanol=9:1) to give the title compound (369.2 mg, 29.7%) as an yellow amorphous.
Reaction SMILES: S([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][CH:7]=1)(O)(=O)=O.[CH:14]1[C:19]([O:20][C:21](Cl)=[O:22])=[CH:18][CH:17]=[C:16]([Cl:24])[CH:15]=1>>[Cl:24][C:16]1[CH:17]=[CH:18][C:19]([O:20][C:21](=[O:22])[N:12]([C:9]2[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=2)[CH3:13])=[CH:14][CH:15]=1
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(Cl)cc1)c1ccc(O)cc1

Procedure:
In analogy to example 15.1, reaction of 4-methylaminophenol hemisulfate with 4-chlorophenylchloroformate yielded (4-Hydroxy-phenyl)-methyl-carbamic acid 4-chloro-phenyl ester, mp: 143-145° C., dec.; MS: 278 (MH+, 1Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[CH:24]=1>>[O:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[CH:24]=[C:20]1[CH2:19][N:16]1[CH:11]([C:4]2[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]1=[O:17]
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: BrCc1cc2ccccc2o1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cc2ccccc2o1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 2-(bromomethyl)benzofuran. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions F): tR=0.83 min.; [M+H]+: 366.15 g/mol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH:19]2[CH2:22][N:21]([C:23](=[O:25])[CH3:24])[CH2:20]2)[CH:5]=[CH:4][N:3]=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32]([OH:36])([C:34]#[CH:35])[CH3:33])[CH:28]=1.C(N(CC)CC)C>CS(C)=O.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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:35]#[C:34][C:32]([OH:36])([C:29]4[CH:28]=[C:27]([CH3:26])[O:31][N:30]=4)[CH3:33])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH:19]2[CH2:22][N:21]([C:23](=[O:25])[CH3:24])[CH2:20]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)N1CC(Oc2nc3ccc(Br)cc3n2-c2ccnc(N)n2)C1
Reactant: C#CC(C)(O)c1cc(C)on1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)N1CC(Oc2nc3ccc(C#CC(C)(O)c4cc(C)on4)cc3n2-c2ccnc(N)n2)C1
Temperature: 70 °C
Reaction time: 5 h
Yield: 21.8 %

Procedure:
A mixture of 1-(3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-one (130 mg, 0.29 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (200 mg, 1.32 mmol), bis(triphenylphosphine)palladium(II) dichloride (250 mg, 0.36 mmol) and triethylamine (1 mL) in DMSO (2 mL) was stirred under nitrogen for 5 h at 70° C. The reaction mixture was cooled to room temperature then filtered through a frit filter. The filtrate was purified by preparative HPLC to give 30 mg (21%) of 1-(3-[[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-one as a white solid: 1H NMR (400 MHz, DMSO) delta 8.41 (d, J=5.6 Hz, 1H), 8.19 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.11-7.07 (m, 3H), 6.45 (s, 1H), 6.38 (s, 1H), 5.57 (t, J=3.6 Hz, 1H), 4.61 (t, J=8.0 Hz, 1H), 4.37-4.29 (m, 2H), 4.03 (t, J=5.2 Hz, 1H), 2.41 (s, 3H), 1.81 (d, J=4.4 Hz, 6H); LC-MS: m/z=+474 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([Cl:14])(=[O:13])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.C1C(=O)N([Br:22])C(=O)C1>C(Cl)Cl>[Br:22][C:4]1[C:5]2[C:10](=[CH:9][C:8]([S:11]([Cl:14])(=[O:13])=[O:12])=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1ccc2ccc(S(=O)(=O)Cl)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cn1cc(Br)c2ccc(S(=O)(=O)Cl)cc21
Reaction time: 2.5 h
Yield: 98.2 %

Procedure:
A solution of 1-methyl-1H-indole-6-sulfonyl chloride (8.764 g, 38.2 mmol) in DCM (190 ml) was treated with n-bromosuccinimide (7.47 g, 42.0 mmol). The resulting mixture was stirred in the dark for 2.5 h, then filtered through a silica gel pad. The filter pad was washed with DCM (2×), and the filtrates were combined. The combined solution was concentrated to give 3-bromo-1-methyl-1H-indole-6-sulfonyl chloride (11.562 g, 37.5 mmol, 98% yield) as an orange solid. 1H NMR (400 MHz, CDCl3) δ=8.08 (dd, J=0.4, 1.7 Hz, 1 H), 7.87-7.80 (m, 1 H), 7.79-7.70 (m, 1 H), 7.42 (s, 1 H), 3.93 (s, 3 H).
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:5][CH:4]([C:6]2([C:9]3[N:14]=[C:13]4[S:15][C:16]([C:18]5[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=5[F:26])=[N:17][C:12]4=[CH:11][CH:10]=3)[CH2:8][CH2:7]2)[CH2:3]1.Cl.[NH:29]1[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]1>>[F:27][C:2]1([F:1])[CH2:3][CH:4]([C:6]2([C:9]3[N:14]=[C:13]4[S:15][C:16]([C:18]5[CH:25]=[CH:24][C:21]([CH2:22][N:29]6[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]6)=[CH:20][C:19]=5[F:26])=[N:17][C:12]4=[CH:11][CH:10]=3)[CH2:7][CH2:8]2)[CH2:5]1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(C5CC(F)(F)C5)CC4)nc3s2)c(F)c1
Reactant: COC(=O)C1CNC1
Agent: Cl
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(C6CC(F)(F)C6)CC5)nc4s3)c(F)c2)C1

Procedure:
Reaction of 4-(5-(1-(3,3-difluorocyclobutyl)cyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-3-fluorobenzaldehyde (112.0 mg, 0.288 mmol) and methyl azetidine-3-carboxylate hydrochloride (65.6 mg, 0.433 mmol) according to Reference R and the general procedure for reductive amination gave methyl 1-(4-(5-(1-(3,3-difluorocyclobutyl)cyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)-3-fluorobenzyl)azetidine-3-carboxylate as a white solid. MS (ESI) m/z: Calculated: 487.2; Observed: 487.8 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:22][CH2:23][N:24]3[CH:29]4[CH2:30][CH2:31][CH:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[S:42]([NH2:45])(=[O:44])=[O:43].[C:46](Br)(=[O:48])[CH3:47]>>[C:46]([NH:45][S:42]([C:3]1[CH:4]=[C:5]([C:8]([N:10]2[CH2:11][CH2:12][C:13]([CH2:22][CH2:23][N:24]3[CH:29]4[CH2:30][CH2:31][CH:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:43])=[O:44])(=[O:48])[CH3:47]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)CC1
Reactant: CC(=O)Br
Product: CC(=O)NS(=O)(=O)c1cc(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3)CC2)ccc1Cl

Procedure:
N-acetyl-2-chloro-5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene-sulfonamide (21.8 mg, quant.) was obtained as amorphous solid from 2-chloro-5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzenesulfonamide and acetyl bromide following the procedure outlined in example 476. 1H NMR (300 MHz, DMSO-d6) 87.85-7.50 (m, 3H), 7.49 (d, J=8.5 Hz, 1H), 7.41-7.35 (m, 5H), 7.25-7.21 (m, 1H), 7.15-7.09 (m, 2H), 4.54 (br, 1H), 3.96 (br, 1H), 3.42-3.29 (m, 5H), 3.06-3.03 (m, 1H), 2.45-2.36 (m, 5H), 2.17-2.07 (m, 2H), 1.98-1.75 (m, 10H), 1.71-1.70 (m, 3H), 1.63-1.61 (m, 2H). HRMS m/z (M+H)+ calcd: 688.2724, obsd: 688.2745.
Reaction SMILES: [F:1][C:2]1[C:6]([F:7])=[CH:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([OH:14])[CH:13]=2)[CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:18]([O:14][C:12]1[CH:13]=[C:8]([N:4]2[CH:3]=[C:2]([F:1])[C:6]([F:7])=[CH:5]2)[CH:9]=[CH:10][C:11]=1[N+:15]([O-:17])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(-n2cc(F)c(F)c2)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2cc(F)c(F)c2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 5-(3,4-difluoro-1H-pyrrol-1-yl)-2-nitrophenol (6.39 g), benzyl bromide (3.48 mL) and potassium carbonate (5.51 g) in DMF (60 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (8.57 g).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[S:3]([O:6][C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1(NCCN1CCS(=O)(=O)CC1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=[O:5])=[O:4].C[C@]12[C@@]3(C)[C@@H]([C@]4(C)[C@@H](CC3)C(C)(C)[C:62](=[O:71])CC4)CCC1[C@H]1[C@H](C(C)=C)CC[C@]1(C=O)CC2>>[F:48][C:2]([F:47])([F:1])[S:3]([O:6][C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([CH:62]=[O:71])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=[O:4])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)C(CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 71 %

Procedure:
The title compound was prepared following the procedure described in method 1 for the preparation of intermediate 1, Step 5, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13bR)-5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbaldehyde as the starting material. (71% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 9.69 (d, J=1.8 Hz, 1H), 5.58 (dd, J=6.7, 2.1 Hz, 1H), 4.89-4.54 (m, 2H), 2.90 (td, J=11.0, 5.8 Hz, 1H), 2.28-2.00 (m, 3H), 2.00-1.64 (m, 7H), 1.60-1.55 (m, 3H), 1.53-1.18 (m, 11H), 1.14 (s, 3H), 1.08 (d, J=7.8 Hz, 1H), 1.03 (s, 3H), 1.00 (s, 3H), 0.97 (s, 3H), 0.93 (s, 3H)
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH:3]=[N:4][C:5]1[S:6][C:7]([CH:13]=[O:14])=[C:8](Cl)[C:9]=1[C:10]#[N:11].[C:16]1([S:22]([O-:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+]>>[CH3:1][N:2]([CH3:15])[CH:3]=[N:4][C:5]1[S:6][C:7]([CH:13]=[O:14])=[C:8]([S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:24])=[O:23])[C:9]=1[C:10]#[N:11]
Reactant: CN(C)C=Nc1sc(C=O)c(Cl)c1C#N
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: CN(C)C=Nc1sc(C=O)c(S(=O)(=O)c2ccccc2)c1C#N

Procedure:
A mixture of 12.1 parts of N,N-dimethyl-N'-(4-chloro-3-cyano-5-formylthien-2-yl)-formamidine, 8.2 parts of sodium phenylsulfinate and 70 parts of methylglycol is heated at the boil for 1 hour. The precipitated product is then filtered off under suction when the mixture is cold and is washed with methylglycol and then with water and dried. 9.7 parts of N,N-dimethyl-N'-(3-cyano-5-formyl-4-phenylsulfonylthien-2-yl)-formamidine are obtained.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH3:16][NH:17][NH2:18]>O1CCOCC1>[CH3:16][N:17]1[C:10](=[O:12])[CH2:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:18]1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CN1N=C(c2ccccc2)CC1=O
Temperature: 500 °C
Reaction time: 8 h

Procedure:
To a mixture of 17.3 ml of ethyl benzoylacetate and 10 ml of water heated to 500° C. was added dropwise 5.3 ml of methyl-hydrazine over a period of 10 minutes (temperature rose to 70° C.) and the resulting mixture was heated at 60° C. for 2 hours. After adding 10 ml of dioxane the mixture was stirred at 55°-65° C. overnight, filtered, and the white solid was washed with water and dried in vacuo (P2O5) to afford 13.23 g of 2,4-dihydro-2-methyl-5-phenyl-3H-pyrazol-3-one (Formula III: R1 =CH3 ; R2 =Ph; R3 =H) as a white solid, m.p. 207° C.(d)
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[CH3:13][OH:14]>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:14][CH3:13])=[O:6])[C:3]=1[C:8]([OH:7])=[O:9]
Reactant: CO
Reactant: O=C1OC(=O)c2c(F)cccc21
Product: COC(=O)c1cccc(F)c1C(=O)O

Procedure:
3-Fluorophthalic anhydride (377 mg, 2.27 mmol) was dissolved in MeOH (6 mL) and heated to reflux for 15 h. The mixture was concentrated in vacuo and the two products (400 mg, 89%), 2-fluoro-6-(methoxycarbonyl)benzoic acid and 3-fluoro-2-(methoxycarbonyl)benzoic acid, were taken on to the next step without purification.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])#[CH:2].CO.[NH3:18]>O1CCCC1>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH2:18])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])#[CH:2]
Reactant: N
Reactant: C#Cc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc(C(N)=O)cc1[N+](=O)[O-]
Yield: 53.2 %

Procedure:
7.3 g (0.036 mol) Methyl 4-ethynyl-3-nitrobenzoate (Compound II-1), 300 ml methanol and 200 ml tetrahydrofuran were added into a reaction flask, stirred, and ammonia gas was passed through for 1 hour. Then the mixture was reacted at room temperature for 24 hours. After completion of the reaction monitored by TLC, the mixture was concentrated under reduced pressure with most of the tetrahydrofuran and methanol evaporated, then extracted with 300 ml ethyl acetate. The organic layer was washed with water for three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, and separated by column chromatography to obtain 4-ethynyl-3-nitrobenzamide (compound I-1), 3.6 g (0.0019 mol), yield 53.2%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=1[OH:21])([CH3:10])([CH3:9])[CH3:8].C1(S(O[C@@H:32]([CH3:37])[C:33]([O:35][CH3:36])=[O:34])(=O)=O)C=CC=CC=1>CS(C)=O>[C:7]([C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=1[O:21][C@H:32]([CH3:37])[C:33]([O:35][CH3:36])=[O:34])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: COC(=O)[C@H](C)OS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)[C@@H](C)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
Potassium carbonate (5.66 g, 41 mmol) and 2,4-di-t-butylphenol (8.87 g, 43 mmol) were dissolved in dimethyl sulfoxide (175 mL) at 25° C. and allowed to stir overnight under a nitrogen atmosphere to ensure complete anion formation. A solution of 10.0 g (41 mmol) of methyl (2S)-2-(phenylsulfonyl)oxypropanate (12) in dimethyl sulfoxide (50 mL) was added to the anion at 25° C. and the reaction mixture was allowed to stir overnight. The reaction was quenched with water (200 mL) and the phases were separated. The aqueous phase was extracted with perchloroethylene (3×200 mL). The combined organic extracts were washed with water (3×300 mL), a saturated aqueous sodium chloride solution (1×300 mL) and dried (MgSO4). Concentration and purification by flash chromatography on silica gel (EM silica gel 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 7 cm diameter×18 cm length) using hexane and ethyl acetate (29:1) afforded 10.1 g (77%) of methyl (2R)-2-(2,4-di-t-butylphenyloxy)propanate (17) as a thick oil: 1H NMR (CDCl3) δ1.29 (s, 9 H), 1.43 (s, 9 H), 1.60-1.65 (d, 3 H), 3.73 (s, 3 H), 4.75-4.82 (q, 1 H), 6.54-6.57 (d, 1 H), 7.08-7.12 (d, 1 H), 7.33 (s, 1 H); 13C NMR (CDCl3) δ172.9, 153.7, 143.0, 137.2, 124.2, 123.1, 110.5, 71.7, 52.0, 5.0, 34.2, 31.5, 29.9, 18.6; IR (neat) 2962 (vs), 1764 (s), 1740 (s), 1497 (s), 1235 (vs) cm-1.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19]([OH:21])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[O:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][NH2:35]>>[CH3:18][N:15]1[C:14]([C:19](=[O:21])[NH:35][CH2:34][C@@H:30]2[CH2:31][CH2:32][CH2:33][O:29]2)=[C:13]([NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)=[O:11])[CH:17]=[N:16]1
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Reactant: NC[C@@H]1CCCO1
Product: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)NC[C@@H]1CCCO1

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (30 mg, 79 μmol; example 236, step 3) and (S)-(tetrahydrofuran-2-yl)methanamine (15 μl, 142 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (31 mg, 84%).
Reaction SMILES: [Na].[OH:2][CH:3]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[CH2:9])[C:4]([O:6][CH3:7])=[O:5].C(O)(=O)C>CO>[CH3:9][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[C:3](=[O:2])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=C(c1ccc(-c2ccc(F)cc2)cc1)C(O)C(=O)OC
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C(=O)C(C)c1ccc(-c2ccc(F)cc2)cc1
Yield: 75.4 %

Procedure:
To a solution of 0.55 g of metallic sodium in 50 ml of anhydrous methanol was added a solution of 6.1 g of methyl 2-hydroxy-3-(4'-fluoro-4-biphenylyl)-3-butenoate in 20 ml of anhydrous methanol. The resulting mixture was refluxed for 20 minutes and then cooled, and the reaction liquid was charged with 5 ml of glacial acetic acid. The mixture was distilled at a low temperature and under reduced pressure to remove the methanol therefrom. To the residue were added ethyl acetate and water, thereby effecting ethyl acetate extraction. The ethyl acetate layer was successively washed with water, aqueous sodium bicarbonate solution and water. The ethyl acetate was removed by distillation under reduced pressure to obtain crude crystals. 5.4 Grams of the crude crystals was recrystallized from ethanol to obtain 4.6 g of methyl 3-methyl-3-(4'-fluoro-4-biphenylyl)-pyruvate, m.p. 100.0°-101.6° C. The yield was 75%.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.Cl[C:8]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=1[C:10]#[N:11].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:8]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=2[C:10]#[N:11])[N:3]=1
Reactant: Cc1nc[nH]n1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2C#N)n1
Temperature: 70 °C
Yield: 58 %

Procedure:
Step G (1): A mixture of 3-methyl-1H-1,2,4-triazole (6.83 g, 82 mmol), 2-chloro-5-nitrobenzonitrile (15 g, 82 mmol), and potassium carbonate (34.1 g, 246 mmol) in anhydrous acetonitrile (200 mL) was heated at 70° C. for 16 h. The dark brown reaction mixture was allowed to cool to rt and was poured into water (500 mL). The aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified using silica gel chromatography (40-100% ethyl acetate/hexane, linear gradient) to afford 2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrobenzonitrile (10.9 g, 58% yield). LC-MS (M+H)+=230.1. 1H NMR (500 MHz, chloroform-D) δ ppm 2.53 (s, 3 H) 8.10 (d, J=9.16 Hz, 1 H) 8.56 (dd, J=9.16, 2.44 Hz, 1 H) 8.68 (d, J=2.44 Hz, 1 H) 8.93 (s, 1 H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:17]([CH3:25])([CH2:18][CH2:19][C:20]=32)[C@@H:11]([C@@H:12]([CH3:16])[CH2:13][CH:14]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:27])[CH3:26].[CH3:28][NH:29][CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:28][N:29]([CH2:14][CH2:13][C@@H:12]([C@@H:11]1[C@:17]2([CH3:25])[C:8]([C:7]3[CH2:6][CH2:5][C@@H:4]4[C@:21]([C:20]=3[CH2:19][CH2:18]2)([CH3:24])[CH2:22][CH2:23][C@H:2]([OH:1])[C:3]4([CH3:26])[CH3:27])=[CH:9][CH2:10]1)[CH3:16])[CH3:30]
Reactant: C[C@@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@@H](CCN(C)C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-carbaldehyde was treated with N,N-dimethylamin and sodium tris(acetoxy)borohydride as described in Example 9d). (20S)-20-[(N,N-dimethylamino)ethyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.