Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C1C(=O)N(Cl)C(=O)C1.[NH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31](=[O:40])[N:32]([CH3:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31](=[O:40])[N:32]([CH3:39])[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:28][CH:29]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(S(=O)[O-])cc1
Reactant: CN(C(=O)Oc1ccc(CCN)cc1)c1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(S(=O)(=O)NCCc2ccc(OC(=O)N(C)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (4-bromo-phenyl)-dimethylamine (4.02 g, 20 mmol) in THF (25 mL) was added dropwise 1.57 M solution in hexanes n-BuLi (11.5 mL, 18 mmol) over a 5-min period at −78° C. The mixture was stirred at −78° C. for 15 min. Then gaseous sulphur dioxide (ca. 5 g) was added causing an immediate precipitation. The mixture was allowed to warm to room temperature and stirred for 1 h. The precipitated lithium sulfinate was isolated by filtration under N2 (g), washed with THF (20 mL) and dried in vacuo providing 2.99 g (87%) of lithium; 4-dimethylamino-benzenesulfinate as a bluegreen solid. This lithium sulfinate (65 mg, 0.34 mmol) was suspended in CH2Cl2 (1 mL) and stirred with NCS (45 mg, 0.34 mmol) for 10 min at rt. A solution of N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.26 mmol) in CH2Cl2 (1.5 mL) was added together with DIPEA (0.90 mmol). The mixture was stirred at rt for 16 h and quenched with HOAc (2 mL) and water (2 mL). Extraction with CH2Cl2 and drying of the combined organic extracts gave the crude product which was purified by preparative HPLC (Gilson). This gave 37 mg (31%) of the title compound as an oil.
Reaction SMILES: C[O:2][C:3](=[O:65])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([C:15](=[O:17])[CH3:16])=[CH:13][CH:14]=2)=[CH:6][C:5]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:29]3[CH:37]=[CH:38][C:39]([C:41]4[N:42]=[N:43][N:44]([C:46]([C:59]5[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=5)([C:53]5[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=5)[C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)[N:45]=4)=[CH:40][C:28]=3[N:27]=2)=[CH:22][CH:21]=1.[OH-].[Li+].C1COCC1.Cl>O.C(O)C>[CH:31]1([N:30]2[C:29]3[CH:37]=[CH:38][C:39]([C:41]4[N:42]=[N:43][N:44]([C:46]([C:53]5[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=5)([C:59]5[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=5)[C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)[N:45]=4)=[CH:40][C:28]=3[N:27]=[C:26]2[C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:18][C:5]3[CH:6]=[C:7]([C:10]4[S:11][C:12]([C:15](=[O:17])[CH3:16])=[CH:13][CH:14]=4)[CH:8]=[CH:9][C:4]=3[C:3]([OH:65])=[O:2])=[CH:25][CH:24]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COC(=O)c1ccc(-c2ccc(C(C)=O)s2)cc1COc1ccc(-c2nc3cc(-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)ccc3n2C2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(C(=O)O)c(COc3ccc(-c4nc5cc(-c6nnn(C(c7ccccc7)(c7ccccc7)c7ccccc7)n6)ccc5n4C4CCCCC4)cc3)c2)s1
Yield: 90 %

Procedure:
A mixture of compound 39 (169 mg, 0.19 mmol) and lithium hydroxide (23 mg, 0.97 mmol) in water (1 mL), ethanol (2 mL), and THF (2 mL) was stirred under reflux for 3 h and cooled and acidified with dilute hydrochloric acid to precipitate 40 which was dried in vacuo to afford 147 mg (90% yield). ESI MS m/e 862 (M+1)
Reaction SMILES: F[P-](F)(F)(F)(F)F.[CH2:8](C1N=NN(O[P+](N(C)C)(N(C)C)N(C)C)C=1)[C:9]1C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C@:38]([N:46]2[C:54]3[C:49](=[C:50]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:51]=[CH:52][CH:53]=3)[CH:48]=[CH:47]2)([CH2:44][CH3:45])/[C:39](=[N:42]\[H])/[NH:40][OH:41])=[CH:34][CH:33]=1.[C:60](O)(=O)C.C(N(CC)C(C)C)(C)C>C(#N)C.O>[CH3:60][CH2:59][S:56]([NH:55][C:50]1[CH:51]=[CH:52][CH:53]=[C:54]2[C:49]=1[CH:48]=[CH:47][N:46]2[C@:38]([C:35]1[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=1)([C:39]1[N:42]=[C:8]([CH3:9])[O:41][N:40]=1)[CH2:44][CH3:45])(=[O:58])=[O:57]
Reactant: [H]/N=C(/NO)[C@@](CC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: CN(C)[P+](On1cc(Cc2ccccc2)nn1)(N(C)C)N(C)C
Reactant: CC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC[C@@](c1ccc(Cl)cc1)(c1noc(C)n1)n1ccc2c(NS(=O)(=O)CC)cccc21
Temperature: 25 °C
Reaction time: 0.01 h

Procedure:
(Benzyltriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (37 mg, 0.083 mmol) was added to a mixture of 5b (35 mg, 0.083 mmol), acetic acid (4.8 μL, 0.083 mmol) and N,N-diisopropylethylamine (29 μL, 0.166 mmol) in acetonitrile (1.50 mL). The resulting mixture was stirred at rt for 30 sec, then heated in a microwave reactor at 150° C. for 20 min. After cooling to rt, the reaction mixture was diluted with water, and the mixture was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (CH3CN/H2O as eluent, 0.05% TFA as modifier), followed by lyophilization of the purified fractions to afford the title compound 57. m/z (ES) 445 (MH)+; IP=A rating
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:31])=O)=[N:27][CH:28]=1)=[O:21].C1C2C(=CC=CC=2)CN1[C:41](NC1C=CC(C(O)=O)=CC=1)=[O:42]>>[O:42]1[CH2:1][CH2:7][CH:8]([CH2:9][NH:10][C:29]([C:26]2[N:27]=[CH:28][C:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13]3)=[O:21])=[CH:24][CH:25]=2)=[O:31])[CH2:41]1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cn1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: NCCCc1ccccc1
Product: O=C(NCC1CCOC1)c1ccc(NC(=O)N2Cc3ccccc3C2)cn1

Procedure:
The title compound was prepared as described in Example 1C, substituting (tetrahydrofuran-3-yl)methanamine for 3-phenylpropan-1-amine and 5-(isoindoline-2-carboxamido)picolinic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.87 (m, 2H), 8.78 (t, J=6.1 Hz, 1H), 8.18 (dd, J=8.5, 2.5 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.42-7.26 (m, 4H), 4.81 (m, 4H), 3.75 (m, 1H), 3.70-3.56 (m, 2H), 3.47 (dd, J=8.5, 5.3 Hz, 1H), 3.27 (m, 2H), 2.53 (m, 1H), 1.91 (m, 1H), 1.61 (m, 1H); MS (ESI(+)) m/e 368 (M+H)+.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH:14]([C:17]1[C:21]([O:22][C:23]2[CH:24]=[C:25]([C:31]#[N:32])[CH:26]=[C:27]([CH:30]=2)[C:28]#[N:29])=[C:20]([CH3:33])[NH:19][N:18]=1)([CH3:16])[CH3:15]>CN(C)C=O>[Si:7]([O:6][CH2:5][CH2:4][N:19]1[C:20]([CH3:33])=[C:21]([O:22][C:23]2[CH:24]=[C:25]([C:31]#[N:32])[CH:26]=[C:27]([CH:30]=2)[C:28]#[N:29])[C:17]([CH:14]([CH3:16])[CH3:15])=[N:18]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1[nH]nc(C(C)C)c1Oc1cc(C#N)cc(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Oc2cc(C#N)cc(C#N)c2)c(C(C)C)nn1CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 45 mg, 1.12 mmol) was added to a stirred solution of 2-bromoethoxy-t-butyldimethylsilane (270 mg, 1.12 mmol) and the pyrazole of Example 95 (250 mg, 0.930 mmol) in N,N-dimethylformamide (5 ml) at 0° C. under nitrogen. The reaction was warmed to room temperature and stirred for 12 hours. The reaction mixture was quenched by the addition of water (50 ml) and the aqueous phase was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a brown oil. The crude product was purified by flash column chromatography on silica gel eluting pentane:ethyl acetate (80:20, by volume) to provide the title compound (60 mg) as a colourless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:26])[CH:24]=O)[CH3:2].C(O)(=O)C(O)=O.[CH2:33]([O:35][P:36]([CH2:41][CH2:42][NH2:43])(=[O:40])[O:37][CH2:38][CH3:39])[CH3:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH2:38]([O:37][P:36]([CH2:41][CH2:42][NH:43][CH2:26][C:23]([CH3:24])=[CH:22][CH2:21][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])=[C:6]2[C:10](=[C:11]([CH3:12])[C:3]=1[CH2:1][CH3:2])[CH2:9][O:8][C:7]2=[O:13])(=[O:40])[O:35][CH2:33][CH3:34])[CH3:39]
Reactant: CCc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)C=O)C(=O)OC2
Reactant: CCOP(=O)(CCN)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOP(=O)(CCNCC(C)=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Reaction time: 4 h
Yield: 98.7 %

Procedure:
4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal (19.7 mg, 0.052 mmol) and aminoethylphosphonic acid diethylester oxalate salt (15.6 mg, 0.057 mmol) were dissolved in DMF (0.5 mL). Acetic acid (15.7 mg, 0.263 mmol) was added, followed by sodium triacetoxyborohydride (22.3 mg, 0.105 mmol). After 4 hrs, the crude reaction mixture was purified by RP-HPLC (eluent: water/MeCN) to provide 27.7 mg (97%) of the desired product after lyophilization. 1H NMR (300 MHz, CDCl3): δ=0.04 (s, 9H), 1.14 (t, J=7.5 Hz, 3H), 1.26 (m, 2H), 1.30 (t, J=7.2 Hz, 6H), 1.95 (s, 3H), 2.19 (s, 3H), 2.23 (m, 2H), 2.68 (q, J=7.5 Hz, 2H), 3.18 (m, 2H), 3.53 (s, 2H), 4.13 (m, 4H), 4.28 (m, 2H), 5.15 (s, 2H), 5.51 (m, 1H) ppm; 31P NMR (121 MHz, CDCl3): δ=27.39 ppm; MS=540 [M++1].
Reaction SMILES: [C:1]1([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH:19]=[C:20]([C:23]#[N:24])[C:21]#[N:22])[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O.O>O1CCCC1>[C:1]1([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH2:19][CH:20]([C:23]#[N:24])[C:21]#[N:22])[CH2:17][CH2:18]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2
Reactant: N#CC(C#N)=C[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: C1CCOC1
Solvent: O
Product: N#CC(C#N)C[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methylene}malononitrile (25.8 mg, 0.0812 mmol) in tetrahydrofuran (3 mL) was mixed with diethyl 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (30.8 mg, 0.122 mmol) and stirred at room temperature for 1 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→1/2→0/1 (v/v)) to give the title compound as a colorless solid (14.2 mg, yield 55%).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH:31]1(B(O)O)[CH2:34][CH2:33][CH2:32]1.N1C=CC=CC=1>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:31]1([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH2:34][CH2:33][CH2:32]1
Reactant: OB(O)C1CCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3C2CCC2)CC1
Yield: 14 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), cyclobutylboronic acid (commercially available), copper(II) acetate and pyridine using chloroform as solvent and stirring under reflux for 6 days, to give the desired product as a light brown foam (14%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[CH:19][C:18]4=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[C:26]([CH:30]=O)[CH:27]=[N:28][CH:29]=5)[N:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:32][S:33]([CH2:36][CH2:37][NH2:38])(=[O:35])=[O:34].Cl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:32][S:33]([CH2:36][CH2:37][NH:38][CH2:30][C:26]1[CH:25]=[C:24]([C:23]2[N:17]3[C:18]([CH:19]=[N:20][C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[CH:13][CH:12]=4)=[N:16]3)=[CH:21][CH:22]=2)[CH:29]=[N:28][CH:27]=1)(=[O:35])=[O:34]
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cncc(C=O)c5)n4n3)cc2)CC1
Reactant: CS(=O)(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cncc(CNCCS(C)(=O)=O)c5)n4n3)cc2)CC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 6 %

Procedure:
Into a 8-dram vial, 5-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-pyridine-3-carbaldehyde (100.2 mg, 0.2424 mmol), 2-Methanesulfonyl-ethylamine; hydrochloride (0.2322 g, 1.454 mmol), 1,2-Dichloroethane (15.0 mL), and Acetic acid (100.0 uL, 1.759 mmol) were added and heated at 45° C. overnight. Sodium triacetoxyborohydride (0.1541 g, 0.7273 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction was partitioned with saturated NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (5 to 25% methanol). The collected fractions afforded (7-{5-[(2-Methanesulfonyl-ethylamino)-methyl]-pyridin-3-yl}-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as a yellow solid (8 mg, 6%). LCMS (E/I+) 521.19 (M+H). NMR 1H (DMSO-d6)-9.27 (s, 1H), 9.19 (d, 1H, J=2.25 Hz), 8.97 (s, 1H), 8.57 (t, 1H, J=1.90 Hz), 8.52 (d, 1H, J=1.61 Hz), 7.56 (d, 2H, J=8.79 Hz), 7.27 (d, 1H, J=5.28 Hz), 6.95 (d, 1H, J=5.28 Hz), 6.92 (d, 1H, J=8.79 Hz), 3.84 (d, 2H, J=5.80 Hz), 3.25 (t, 2H, J=6.63 Hz), 3.08 (t, 4H, J=4.97 Hz), 3.00 (s, 3H), 2.94 (q, 2H, J=6.63 Hz), 2.46 (t, 4H, J=4.97 Hz), 2.24 (s, 3H).
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.[CH3:26][NH:27][CH2:28][CH2:29][CH:30]1[O:35][CH2:34][CH2:33][NH:32][CH2:31]1>>[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]([N:32]3[CH2:33][CH2:34][O:35][CH:30]([CH2:29][CH2:28][NH:27][CH3:26])[CH2:31]3)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: CNCCC1CNCCO1
Product: CNCCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c2F)CCO1

Procedure:
By the use of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(2 -methylaminoethyl)morpholine, the reaction is similarly carried but as Example 26 to give 1-(2,4-difluorophenyl)-6,8-difluoro-1,4-dihydro-7-[2-(2-methylaminoethyl)morpholino]-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=O)[O:3]C1=O.[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>CN(C=O)C.O>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([Br:13])[C:15]=1[CH3:21])=[O:3]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Cc1c(N)cccc1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)cccc1NC(=O)c1ccccc1N
Yield: 5.9 %

Procedure:
A suspension of 1H-benzo[d][1,3]oxazine-2,4-dione (10.00 g, 61.3 mmol) in DMF (150 mL) was treated with 3-bromo-2-methylaniline (13.69 g, 73.6 mmol) and heated to reflux overnight. The cooled mixture was diluted with water and extracted with EtOAc. The whole mixture was filtered to remove grey solids and the layers of the filtrate were separated. The organic phase was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (330 g), eluting with EtOAc-hexanes (gradient from 0-50%), to give 2-amino-N-(3-bromo-2-methylphenyl)benzamide as tan solid (1.1 g, 6% yield). A second eluent from the column gave 3-(3-bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 4B] as a tan solid (3.4 g, 17% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][NH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:24]#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][N:11]([CH:23]([C:24]#[N:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]=1[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1OCc1ccccc1
Reactant: N#CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn(C(C#N)c2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of dimethyl 4-benzyloxy-1H-pyrazole-3,5-dicarboxylate (1.0 g, 3.45 mmol) and bromo(phenyl)acetonitrile (810 mg, 4.13 mmol) in anhydrous DMF was treated with Cs2CO3 (1.46 g, 4.48 mmol) and stirred at room temperature for 3 days. The solvent was removed in vacuo and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc several times, and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel using a gradient elution of 0-20% EtOAc/hexanes. Collection and concentration of the appropriate fractions yielded the title product as a yellow oil. 1H NMR (400 MHz, d6-DMSO) δ 7.70 (s, 1H), 7.50-7.45 (m, 3H), 7.43-7.29 (m, 7H), 5.08 (s, 2H), 3.86 (s, 3H), 3.81 (s, 3H); ES MS (M+1)=406.
Reaction SMILES: [N+:1]([N:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C(#N)C>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18](=[O:23])[CH2:17][N:6]1[CH2:7][CH2:8][NH:9][C:5]1=[N:4][N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])N=C1NCCN1
Reactant: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)C(=O)CN1CCNC1=N[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A mixture of 2.6 g of 2-nitroimino-imidazolidine, 3.0 g of anhydrous potassium carbonate and 30 ml of dry acetonitrile was stirred at room temperature for 30 minutes. Then, 2.7 g of 1-chloro-3,3-dimethyl-2-butanone were added to the mixture under stirring at room temperature. The reaction mixture was heated and refluxed for 1 hour. The acetonitrile was distilled off under a reduced pressure, and the residue was admixed with water. The aimed product was separated by filtration. The crystalline product was washed in ether and dried. 3.5 g of 1-(3,3-dimethyl-2-butanon-1-yl)-2-nitroimino-imidazolidine were obtained. mp. 158°-159° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:3]=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>>[CH:25]1([C:28]([NH:1][C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH:11]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:23])([F:22])[F:24])=[CH:17][CH:18]=3)[CH3:12])=[O:9])[CH:3]=2)=[O:29])[CH2:27][CH2:26]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(NC(=O)c1cc(N)ncn1)c1ccc(OCC(F)(F)F)nc1
Product: CC(NC(=O)c1cc(NC(=O)C2CC2)ncn1)c1ccc(OCC(F)(F)F)nc1

Procedure:
The title compound is prepared from 6-amino-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (30 mg, 0.09 mmol, Step-1 of Example 117, single enantiomer) and cyclopropanecarbonyl chloride (14 mg, 0.13 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [O:1]1[C:19]2=[C:20]3[C@:15]([CH3:22])([CH2:16][CH2:17][C:18]2=[O:21])[C@@H:14]2[C@H:4]([C@H:5]4[C@:11]([CH3:23])([CH2:12][CH2:13]2)[C@@H:8]([CH2:9][CH3:10])[CH2:7][CH2:6]4)[C@@H:3]2[O:24][C@:2]123.C(O)C.[BH4-].[Na+].Cl>O>[O:1]1[C:19]2=[C:20]3[C@:15]([CH3:22])([CH2:16][CH2:17][C@@H:18]2[OH:21])[C@@H:14]2[C@H:4]([C@H:5]4[C@:11]([CH3:23])([CH2:12][CH2:13]2)[C@@H:8]([CH2:9][CH3:10])[CH2:7][CH2:6]4)[C@@H:3]2[O:24][C@:2]123
Reactant: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4=O)[C@H]3CC[C@]12C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4O)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 0.105 g (0.237 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3-one and 6 ml of ethanol was added 9 mg (0.237 mmole) of sodium borohydride at a temperature of 0° C. and the mixture was stirred at 0° C. for 30 minutes. To the reaction mixture were added water and 1N-hydrochloric acid in the order mentioned and the mixture was extracted with methylene chloride. The aqueous layer was further extracted with methylene chloride and the extract was pooled with the previous methylene chloride extract. The mixture was washed successively with cold saturated sodium hydrogen carbonate solution and aqueous sodium chloride solution and the organic layer was dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:10, v/v) to recover 0.084 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3β-ol (yield: 80%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([CH2:22][S:23]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:36]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.Cl.O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:16]=[C:17]3[C:18](=[CH:19][CH:20]=2)[NH:21][N:36]=[C:22]3[S:23]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OC2CCCN(Cc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCCN(Cc4ccccc4)C3)cc12

Procedure:
A mixture of 4-(1-benzylpiperidin-3-yloxy)-2-(1-naphthylsulfonylmethyl)phenylamine (1.0 g, 2 mmoles) in THF and 4M HCl (10 mL), under nitrogen, at 3° C. was treated dropwise with a solution of sodium nitrite (0.16 g, 2.4 mmoles) in H2O, poured into a cold solution of saturated sodium bicarbonate and extracted with EtOAc. The extracts were combined, dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.7 g, 1.4 mmoles).