Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:6][NH:7][CH2:8][CH2:9][CH2:10][CH:11]1[NH:15]C(=O)N[C:12]1=[O:17])(OCC)=O.[OH2:18].O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>O>[NH2:15][CH:11]([CH2:10][CH2:9][CH2:8][NH:7][NH2:6])[C:12]([OH:17])=[O:18]
Reactant: CCOC(=O)NNCCCC1NC(=O)NC1=O
Reactant: O
Agent: [Ba+2]
Agent: [OH-]
Product: NNCCCC(N)C(=O)O

Procedure:
Mix 5-[3-(carbethoxyhydrazino)-propyl]-hydantoin (2.44 g, 10 mmol), barium hydroxide octahydrate (18.15 g, 10 mmol) and water (55 mL). Reflux for 12 hours, remove the white solid by filtration and extract the filter cake with boiling water (25 ml) and finally wash with hot water (25 mL). Combine the filtrate and washings, treat with ammonium carbonate (5.7 g) and heat with stirring. Filter off the barium carbonate, wash the filter cake with hot water and evaporate the filtrate and washings in vacuo to give 2-amino-5-hydrazino- pentanoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6](=[O:18])[C:5]2(O)[C:19]1[C:28]([OH:29])=[CH:27][C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=1.FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6](=[O:18])[CH:5]2[C:19]1[C:28]([OH:29])=[CH:27][C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=1
Reactant: O=C1N(Cc2ccccn2)c2ccc(Br)cc2C1(O)c1cc2c(cc1O)OCCO2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2cc3c(cc2O)OCCO3)c2cc(Br)ccc2N1Cc1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.8 %

Procedure:
To a suspension of 5-bromo-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one (3.60 g, 8.10 mmol) in triethylsilane (10 mL) at 0° C. was added trifluoroacetic acid (40 mL). The solution was allowed to warm to ambient temperature over 2 h and was stirred for a further 4 h. The reaction mixture was concentrated in vacuo and saturated aqueous sodium bicarbonate and ethyl acetate were added to the residue, causing a precipitate to be deposited. The solid was collected by filtration and washed sequentially with diethyl ether and hexanes to afford 5-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one (4.03 g, 100%) as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 8.59-8.55 (m, 1H), 7.90-7.80 (m, 1H), 7.44-7.37 (m, 1H), 7.34-7.27 (m, 1H), 7.07 (s, 1H), 6.82-6.68 (m, 2H), 6.27 (s, 1H), 5.17-4.93 (m, 2H), 4.84 (s, 1H), 4.23-4.06 (m, 4H). MS (ES+) m/z 452.9 (M+1), 454.9 (M+1).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27](OC)=[C:28]([O:31][CH2:32][CH2:33][CH2:34]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:38]5[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=S1(=O)CCNCC1
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Sc3ncnc4ccc(OCCCN5CCS(=O)(=O)CC5)cc34)c2)no1
Yield: 43 %

Procedure:
The title compound was prepared as described in Example 57B by using 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea from the previous step (230 mg, 0.45 mmol), thiomorpholine 1,1-dioxide (182 mg, 1.35 mmol), tetrabutylammonium iodide (166 mg, 0.45 mmol) and N,N′-diisopropylethylamine (160 μL, 0.89 mmol) in N,N′-dimethylformamide (3 mL) to afford 1-(5-tert-Butyl-isoxazol-3-yl)-3-(3-{6-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-quinazolin-4-ylsulfanyl}-phenyl)-urea (117 mg, 43%) as solid. 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.03 (s, 1H), 8.75 (s, 1H), 7.94-7.86 (m, 2H), 7.68 (d, 1H), 7.51-7.41 (m, 3H), 7.30 (d, 1H), 6.49 (s, 1H), 4.26-4.23 (m, 2H), 3.11 (bs, 4H), 2.95 (bs, 4H), 2.71-2.67 (m, 2H), 2.00-1.96 (m, 2H), 1.27 (s, m 9H); LC-MS (ESI) m/z 611 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:5][CH2:6][CH:7]([OH:9])[CH3:8])[CH3:4].Cl[C:11]1([N:36]=[N:37][C:38]2[N:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:16]=[CH:15][C:14]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:13][NH:12]1>O1CCCC1>[CH2:3]([N:5]([CH2:6][CH:7]([OH:9])[CH3:8])[C:11]1([N:36]=[N:37][C:38]2[N:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:16]=[CH:15][C:14]([C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:13][NH:12]1)[CH3:4]
Reactant: CCNCC(C)O
Reactant: ClC1(N=Nc2cccnn2)C=CC(C(c2ccccc2)(c2ccccc2)c2ccccc2)=NN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC(C)O)C1(N=Nc2cccnn2)C=CC(C(c2ccccc2)(c2ccccc2)c2ccccc2)=NN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
To a 50% suspension of 1.5 g sodium hydride in 100 ml tetrahydrofuran, 3 g ethyl-(2-hydroxypropyl)amine are added; this is stirred at room temperature for 30 minutes, thereafter 4.5 g of 3-chloro-6-triphenylmethylazopyridazine are added. Stirring is maintained for 5 minutes, the organic phase is washed with a saturated solution of sodium chloride, rendered anhydrous and evaporated to dryness under a vacuum. The residue is taken up with ethyl alcohol, diluted with water, and the precipitate is collected under a vacuum which is then triturated with diisopropyl ether to yield 4 g of 3-[ethyl-(2-hydroxypropyl)amino]-6-triphenylmethylazopyridazine melting at 137° C. (with decomposition). A solution of 3 g of 3-[ethyl-(2-hydroxypropyl)amino]-6-triphenylmethylazopyridazine in 300 ml ethyl alcohol and 50 ml tetrahydrofuran containing 300 mg 5% palladium on carbon is hydrogenated at room temperature and pressure. The catalyst is filtered out, then the residue is evaporated and triturated with diethyl ether to yield 2.5 g of 3-[ethyl-(2-hydroxypropyl)amino]-6-(2-triphenylmethylhydrazino)pyridazine melting at 122° C. (with decomposition). A solution of 2 g of 3-[ethyl-(2-hydroxypropyl)amino]-6-(2-triphenylmethylhydrazino)pyridazine in 100 ml absolute ethyl alcohol is mixed with 2.5 ml concentrated hydrochloric acid and stirred for 15 minutes at room temperature. This is evaporated under a vacuum and the residue taken up with isopropyl alcohol. This is diluted with diisopropyl ether to yield 1.2 g of 3-[ethyl-(2-hydroxypropyl)amino]-6-hydrazinopyridazine dihydrochloride melting at 208°-212° C. (with decomposition).
Reaction SMILES: [CH:1]([CH:4]1[C:9](=O)[NH:8][CH2:7][CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:3])[CH3:2].Br[C:19]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:20]=1[NH2:21].CN[C@@H]1CCCC[C@@H]1NC>CN1C(=O)CCC1.O.[Cu]I>[CH:1]([CH:4]1[N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:7][N:8]2[C:19]3[CH:25]=[C:24]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:23]=[CH:22][C:20]=3[N:21]=[C:9]12)([CH3:3])[CH3:2]
Reactant: CC(C)C1C(=O)NCCN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1ccc(N)c(Br)c1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@H]1NC
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1C(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
To a solution of tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (200 mg, 0.83 mmol) in NMP (3 mL) were added 2-bromo-4-(methylsulfonyl)aniline (207 mg, 0.83 mmol), (1R,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (12.0 mg, 0.08 mmol), K3PO4.3H2O (660 mg, 2.48 mmol) and CuI (16 mg, 0.08 mmol). The mixture was stirred at 150° C. for 1 h in a microwave oven. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative TLC with CH2Cl2/MeOH 35/1 to afford tert-butyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (110 mg, 34% yield) as a white solid. LC-MS m/z 394.1 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 7.94 (s, 1H), 7.83-7.76 (m, 2H), 5.35-5.17 (m, 1H), 4.73-4.42 (m, 1H), 4.22-4.12 (m, 1H), 4.11-3.99 (m, 1H), 3.53-3.37 (m, 1H), 3.03 (s, 3H), 2.38-2.27 (m, 1H), 1.42 (s, 9H), 1.19 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H).
Reaction SMILES: C[N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1N1CCCCC1C)[C:3](=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[Cl:32][C:33]1[N:38]=[C:37](B(O)O)[CH:36]=[CH:35][CH:34]=1>>[Cl:32][C:33]1[N:38]=[C:37]([C:24]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[NH:2][CH3:3])[CH:36]=[CH:35][CH:34]=1
Reactant: OB(O)c1cccc(Cl)n1
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CNc1cnccc1-c1cccc(Cl)n1

Procedure:
The title compound was prepared in analogy to example 68, intermediate, from (4-bromo-pyridin-3-yl)-methyl-amine (example 25, intermediate b) and 6-chloropyridine-2-boronic acid (CAS RN 652148-90-8). Brown sticky solid (90%). MS (ESI): m/z=220.0 [M+H]+.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Br[C:6]1[S:7][CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=1>C1(C)C=CC=CC=1>[CH:1]1([NH:4][C:6]2[S:7][CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: NC1CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1csc(NC2CC2)n1

Procedure:
The reaction described in Preparation 26 was repeated, except that a mixture comprising 2.28 g of cyclopropylamine, 5.0 g of ethyl 2-bromothiazole-4-carboxylate and 20 ml of toluene was heated at 100°-110 ° C. for 16 hours in a sealed tube, giving the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[S:7].C(#N)C.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C>[CH3:1][NH:2][C:3]1[S:7][C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][CH:4]=1
Reactant: CNC(=O)CNC(=S)c1cccnc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CNc1cnc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
To a dry 2 L round bottom flask equipped with mechanical stirrer, addition funnel and reflux condenser was charged N-methyl-2-(pyridine-3-carbothioamido)acetamide (100 g, 478 mmol) and acetonitrile (1 L). To this mixture was added phosphorus oxychloride (256 g, 1672 mmol) portionwise over 10 minutes. The reaction mixture was stirred at ambient temperature for 10 minutes during which time a slight exotherm occurred from 22° C. to 34° C. The reaction mixture was heated to 85° C. (refluxing gently). After 3 hours, all of the solid had dissolved, forming a dark amber solution. Analysis of an aliquot by TLC (70% ethyl acetate : 30% hexanes) after 4 hours indicated that the reaction was essentially complete. The reaction mixture was allowed to cool to 25° C. and the solvent removed by rotary evaporation. The residue was dissolved in water and treated with solid sodium bicarbonate until slightly basic (pH˜8) with continuous stirring. A brown precipitate started to form after a few minutes. The mixture was continued to stir at 25° C. for 16 hours. The brown solid was collected by vacuum filtration and washed with water. This gave a tan solid wet cake (91 g) which was then dried in vacuo at 40° C. to a constant weight. This gave N-methyl-2-(pyridin-3-yl)thiazol-5-amine as a sand colored solid (68.5 g, 75% yield); mp 140-141° C.; 1H NMR (400 MHz, CDCl3) δ 8.98 (dd, J=2.3, 0.7 Hz, 1H), 8.53 (dd, J=4.8, 1.6 Hz, 1H), 8.07 (ddd, J=8.0, 2.2, 1.7 Hz, 1H), 7.40-7.21 (m, 1H), 6.96 (s, 1H), 4.18 (s, 1H), 2.96 (s, 3H); 13C NMR (101 MHz, CDCl3) δ153.23, 149.15, 146.54, 132.23, 130.47, 123.65, 121.20, 34.48; Anal. Calc'd. for C9H9N3S: C, 56.52; H, 4.74; N, 21.97; S, 16.77. Found: C, 56.31: H, 4.74; N, 21.81; S, 16.96.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[CH3:9][O:10][C:11]([C:13]#[C:14][C:15]([O:17][CH3:18])=[O:16])=[O:12]>C(Cl)(Cl)Cl>[O-:8][N+:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1]/[C:13](=[CH:14]\[C:15]([O:17][CH3:18])=[O:16])/[C:11]([O:10][CH3:9])=[O:12]
Reactant: Nc1cccc[n+]1[O-]
Reactant: COC(=O)C#CC(=O)OC
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C(\Nc1cccc[n+]1[O-])C(=O)OC
Reaction time: 1 h

Procedure:
To a stirred solution of 2-aminopyridine-N-oxide in chloroform at 0° C. was added dropwise a solution of DMAD (1 eq.) in chloroform. After addition the cooling bath was removed and stirring was continued for 1 hour. A further 0.2 eq. of DMAD was added and stirring continued for 1 hour. The solution was filtered over a silica gel plug. After elution with EtOAc/PE (4:6), the product was eluted with MeOH/EtOAc. The combined MeOH/EtOAc-phases were concentrated to dryness. The title compound was obtained as a brown oil, which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.CN(C=O)C.[NH4+].[Cl-]>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=2)=[CH:18][CH:19]=1
Reactant: C#Cc1ccc(CC(C)NC(C)=O)cc1
Reactant: Oc1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)Cc1ccc(C#Cc2ccc(O)cc2)cc1
Temperature: 0 °C

Procedure:
4.00 g (19.9 mmol) of N-(1-(4-ethynylphenyl)propan-2-yl)acetamide (I58.3) and 5.25 g (23.9 mmol) 4-iodophenol are added to 125 ml of a 1:1 mixture of DMF and TEA. After cooling down to 0° C. 189 mg (0.99 mmol) CuI and 976 mg (1.39 mmol) Pd(PPh3)4 are added. After stirring over night at r.t. the mixture is treated with EtOAc and sat. NH4Cl solution. The organic layer is washed with brine, dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel, EtOAc).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([O:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[CH2:13][N:12]1[C:25](=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=O)C1C=CC=CC=1>CO>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:25]([N:12]2[CH2:13][CH:14]([O:16][C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:15][NH:11]2)=[O:34])=[CH:28][CH:29]=1
Reactant: O=C(OC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1)N1CCOCC1
Solvent: CO
Product: O=C(OC1CNN(C(=O)Cc2ccc(F)cc2)C1)N1CCOCC1
Reaction time: 2.5 h

Procedure:
morpholine-4-carboxylic acid 1-benzyloxycarbonyl-2-[2-(4-fluorophenyl)acetyl]-pyrazolidin-4-yl ester, 40, (512 mg, 1.09 mmol) is dissolved in methanol (10 mL) and the flask flushed with nitrogen then charged with 10% palladium on carbon (103 mg). The reaction mixture is vigorously stirred and hydrogenated at 1 atmosphere for 2.5 hours at room temperature. The reaction mixture is filtered through a pad of Celite, rinsed with ethyl acetate (100 mL) and concentrated in vacuo to afford 354 mg of the desired product as a white powder.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:25])[CH2:17][C@@H:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[I:26]I>C(O)(=O)C>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:25])[CH:17]([I:26])[C@@H:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: II
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C[C@H](C)[C@]4(C)[C@H]3CC[C@]12C
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C(I)[C@H](C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 24 h
Yield: 93.5 %

Procedure:
6.88 g (20 mmol) of 17β-acetoxy-1α-methyl-androst-4-en-3-one and 1.75 g (22 mmol) of CuO in 60 ml of acetic acid are mixed with stirring at room temperature with 5.58 g (22 mmol) of iodine and stirred under nitrogen atmosphere for 24 hours at 60° C. Under reduced pressure, the acetic acid is largely distilled off and the residue is taken up in 100 ml of water. The water phase is extracted 3 times with 100 ml of ethyl acetate each. The ethyl acetate phases are washed with sodium thiosulfate solution and dried on sodium sulfate. After concentration by evaporation of the solution, 10 g of crude product is obtained. Recrystallization from ethyl acetate yields 8.8 g of 17β-acetoxy-2-iodo-1α-methyl-androst-4-en-3-one (93% of theory) of melting point 102° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[S:13][C:14]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[O:10])=[CH:5][N:4]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.O>CN(C=O)C>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:15]1[N:16]=[C:12]([NH:11][C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[N:4][CH:5]=2)=[O:10])[S:13][C:14]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: c1c[nH]cn1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(CCl)nc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(Cn2ccnc2)nc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
Compound 36 (97.1 mg, 0.240 mmol) was dissolved in DMF (2.5 mL), imidazole (49.0 mg, 0.721 mmol) was added thereto, followed by stirring at 95° C. for 2 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under the reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=17:3) to afford the entitled Compound 37 (58.0 mg, 55%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[Br:13]Br.[Cl-].[Al+3].[Cl-].[Cl-].S([O-])([O-])(=O)=S.[Na+].[Na+]>[Fe].C(OCC)(=O)C.O.ClCCl>[Br:13][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:5]=1
Reactant: BrBr
Reactant: CSc1ccccc1C(F)(F)F
Agent: [Fe]
Agent: O=S([O-])([O-])=S
Agent: [Al+3]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CSc1ccc(Br)cc1C(F)(F)F
Yield: 73.8 %

Procedure:
Combine 1-methylsulfanyl-2-trifluoromethyl-benzene (3.5 g, 18 mmol), iron (100 mg, 1.79 mmol), bromine (0.95 mL, 18 mmol), aluminum chloride (242 mg, 1.8 mmol) and dichloromethane (50 mL) and stir for 2 hours. Add water (10 mL), aqueous saturated sodium thiosulfate (100 mL) and ethyl acetate (100 mL). Separate the organic layer and wash with brine, dry with MgSO4, filter and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with hexane to give 3.6 g of 4-bromo-1-methylsulfanyl-2-trifluoromethyl-benzene (83%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:3]([C:5]2[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:27][CH2:28]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)nn1C
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NC2CCOCC2)n(C)n1
Yield: 51 %

Procedure:
As described for example 78b, 2-methyl-5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (70 mg, 0.21 mmol) was converted using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (43 mg, 51%) which was obtained as a white solid. MS: m/e=398.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([C:18]3[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=3)[O:21]N3CCCCC3)[CH2:14][CH:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:31]=1)[CH3:2].Cl.O1[CH2:38][CH2:37]OCC1>O1CCOCC1>[CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([C:18]3[CH:30]=[CH:29][CH:28]=[C:20]([O:21][CH:38]4[CH2:37][CH2:4][NH:3][CH2:1][CH2:2]4)[CH:19]=3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:31]=1)[CH3:2]
Reactant: C1COCCO1
Reactant: CCNc1ncc2c(n1)N1CCCC1CN(c1cccc(ON3CCCCC3)c1)C2=O
Agent: Cl
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(OC3CCNCC3)c1)C2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
(S)-1-Tert-butoxycarbonyl-4-(3-(9-ethylamino-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenoxypiperidine (0.633 g, 1.21 mmol) obtained in Step 2 was dissolved in 1,4-dioxane (10 mL), and the mixture was stirred at room temperature for 1.5 hours after adding a 4 mol/L hydrochloric acid-1,4-dioxane solution (10 mL). The mixture was concentrated under reduced pressure, diluted with chloroform, and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and crystallized from diethyl ether to give the title compound (Compound 147) (0.420 g, 82%).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:29]2[S:30][CH:31]=[C:32]([CH:34]=O)[N:33]=2)[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26]>C1COCC1.C(OCC)(=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:29]2[S:30][CH:31]=[C:32]([CH:34]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:33]=2)[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(-c2nc(C=O)cs2)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1csc(-c2cc(OC)c(OC)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
THF (5 mL) was added to sodium hydride (55% dispersion in mineral oil, 162 mg) under an argon atmosphere, and a solution of ethyl diethylphosphonoacetate (832 mg) in THF (2 mL) was added dropwise to the mixture at −10° C. After 30 minutes, a solution of 2-(3,4,5-trimethoxyphenyl)thiazole-4-carboaldehyde (942 mg) in THF (8 mL) was slowly added to the resultant mixture, and the mixture was warmed to room temperature over 30 minutes and then stirred for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate. After concentrating the reaction mixture under reduced pressure, the resultant crude crystals were recrystallized from ethyl acetate-hexane to obtain the title compound.
Reaction SMILES: CON(C)[C:4](=[O:9])[CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][Mg]Cl)=[CH:14][CH:13]=1>>[CH3:7][CH:6]([CH3:8])[CH2:5][C:4](=[O:9])[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([CH3:16])=[CH:14][CH:13]=1
Reactant: Cc1ccc(C[Mg]Cl)cc1
Reactant: CON(C)C(=O)CC(C)C
Product: Cc1ccc(CC(=O)CC(C)C)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 36-b) using N-methoxy-N-methyl-3-methylbutanamide and 4-methylbenzyl magnesium chloride to obtain a title compound as a light yellow oily substance.