Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:10])=[N:2]1.S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>>[N+:16]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][N:2]=[C:3]([OH:10])[C:4]=2[CH:9]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: Oc1noc2ccccc12
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2onc(O)c2c1
Reaction time: 1.5 h

Procedure:
1,2-Benzisoxazol-3-ol (19.7 g, 0.146 mol) is added portionwise to concentrated sulfuric acid. The resultant reaction mixture is treated dropwise with 70% nitric acid (11.3 mL), stirred for 90 minutes, and poured onto ice. The resultant aqueous mixture is filtered to obtain a waxy paste. The paste is recrystallized from a methanol/water mixture to give the title product as a solid which is identified by 1H NMR spectral analysis.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:21]2[NH:22][CH2:23][CH2:24][O:25][C:20]=2[CH:19]=1>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:21]3[CH:26]=[CH:27][C:18]([O:17][CH3:16])=[CH:19][C:20]=3[O:25][CH2:24][CH2:23]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1ccc2c(c1)OCCN2
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCOc3cc(OC)ccc32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 556 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. 1H NMR (300 MHz, CDCl3): δ 6.98 (s, 1H), 6.94 (d, J=9.6 Hz, 1H), 6.44-6.41 (m, 2H), 4.33-4.30 (m, 2H), 4.18-4.08 (m, 3H), 3.75 (s, 3H), 1.92-1.78 (m, 2H), 1.10-1.00 (m, 1H), 0.95 (t, J=7.3 Hz, 3H), 0.81-0.77 (m, 1H), 0.60-0.48 (m, 2H), 0.38-0.20 (m, 1H); HRMS (ESI) m/z 376.1452 [(M+H)+, calcd for C19H23N3O3Cl 376.1428].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:18](=[O:20])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:35][C@@H:36]([CH2:49][NH2:50])[CH2:37][O:38][C:39]1[C:47]2[NH:46][C:45](=[O:48])[NH:44][C:43]=2[CH:42]=[CH:41][CH:40]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:29][CH2:30][CH:31]([NH:50][CH2:49][C@H:36]([OH:35])[CH2:37][O:38][C:39]5[C:47]6[NH:46][C:45](=[O:48])[NH:44][C:43]=6[CH:42]=[CH:41][CH:40]=5)[CH2:32][CH2:33]4)=[CH:24][CH:23]=3)[C:18](=[O:20])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(C=C3SC(NC4CCN(Cc5ccccc5)CC4)=NC3=O)cc2)CC1
Product: O=C1N=C(NC2CCN(Cc3ccccc3)CC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 1-{4-[2-(1-benzyl-piperdin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one(which was obtained in Intermediate 21) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedure of Example 1 as a pale yellowish solid; mp>165° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.40-1.65 (m, 2 H), 1.70-2.00 (m, 4 H), 2.06 (brt, J=9.9 Hz, 2 H), 2.55-2.95 (m, 6 H), 3.47 (s, 2 H), 3.75-4.05 (m, 5 H), 4.87 (brs, 1 H), 6.57 (d, J=7.5 Hz, 1 H), 6.61 (d, J=8.1 Hz, 1 H), 6.84 (t, J=8.1 Hz, 1 H), 7.02 (d, J=9.0 Hz, 2 H), 7.20-7.50 (m, 8 H), 9.46 (brs, 1 H), 10.57 (s, 1 H), 10.70 (brs, 1 H); MS (ES) m/z: 341.6 ((M+2H)2+, 100%); 682.1 (MH+, 5%); HRMS Calcd. for C37H44N7O4S (MH+): 682.3176. Found: 682.3211.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6]([CH:21]2[CH2:23][CH2:22]2)=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:9][CH:10]=1.CC(C[AlH]CC(C)C)C>>[CH:21]1([C:6]2[C:5]([CH2:4][CH2:3][OH:2])=[CH:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=3)[N:7]=2)[CH2:23][CH2:22]1
Reactant: COC(=O)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: CC(C)C[AlH]CC(C)C
Product: OCCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1

Procedure:
In analogy to the procedure described in example 1 f], [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid methyl ester was reacted with DIBAL-H to give the title compound as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[H][H]>C(O)C.[Pd]>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([Cl:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: N#Cc1cc(N)ccc1Cl
Yield: 43.1 %

Procedure:
A solution of 10.0 g (54.8 mmol) 2-chloro-5-nitrobenzonitrile in 500 ml ethanol was hydrogenated at 30 psi by using 0.5 g 5% Pd-C as a catalyst When the hydrogen uptake had ceased, the reaction mixture was filtered and evaporated in vacuo. The residue was recrystallized (ethanol-water) to give 3.6 g (44%) of 5-amino-2-chlorobenzonitrile. M.p. 129°-130° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=O.Cl>CO.O>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[CH:31][C:22](/[CH:20]=[CH:15]/[C:14](=[O:16])[C:13]2[C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1cccnc1Nc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(/C=C/C(=O)c2cccnc2Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.7 %

Procedure:
A solution of 1-(2-phenylamino-pyridin-3-yl)-ethanone (2.13 g, 10.0 mmol) in methanol (42 mL, 0.24M) was treated with sodium methoxide (25% wt. solution methanol, 4.6 mL, 20.1 mmol) and methyl 4-formylbenzoate (2.04 g, 12.4 mmol). The reaction was stirred at 25° C. over 3 d. At this time, the reaction was diluted with water (100 mL), acidified with a 1N aqueous hydrochloric acid solution, and extracted with a 10% methanol/methylene chloride solution. The combined organics were dried over magnesium sulfate, filtered, rinsed with methylene chloride, and concentrated onto silica gel in vacuo. Flash chromatography (AnaLogix Intelliflash 280, 80 g silica gel column, 20% ethyl acetate/hexanes) afforded 4-[(E)-3-oxo-3-(2-phenylamino-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (3.43 g, 95%) as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])=[CH:15][CH:14]=1)=[CH:9][C:8]([Br:24])=[CH:7][CH:6]=2.C(N(CC)CC)C.Cl[C:33](OC(Cl)(Cl)Cl)=[O:34]>C(Cl)Cl>[Br:24][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[NH:1][C:33](=[O:34])[N:12]([C:13]4[CH:14]=[CH:15][C:16]([C:19]([CH3:22])([CH3:23])[C:20]#[N:21])=[CH:17][CH:18]=4)[C:11]=3[C:10]=2[CH:9]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C#N)c1ccc(Nc2c(N)cnc3ccc(Br)cc23)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reaction time: 0.33 h

Procedure:
A solution of 5 g (13.1 mmol) of 2-[4-(3-amino-6-bromo-quinolin-4-ylamino)-phenyl]-2-methyl-propionitrile (Example 1g) and 1.59 g (15.7 mmol) of triethylamine in 120 ml CH2Cl2 is added over 40 min to a solution of 2.85 g (14.4 mmol) of trichloromethyl chloroformate (Fluka, Buchs, Switzerland) in 80 ml of CH2Cl2 at 0° C. with an ice-bath. The reaction mixture is stirred for 20 min at this temperature then is quenched with sat. aqueous NaHCO3, stirred for 5 min and extracted with CH2Cl2. The organic layer is dried over Na2SO4, filtered and evaporated in vacuo to give crude title compound as a brownish solid. ES-MS: 407, 409 (M+H)+, Br pattern; analytical HPLC: tret=3.05 min (Grad 1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]2[C:10](=[S:13])[NH:11][N:12]=[C:8]2[CH:7]=[C:6]([F:14])[N:5]=1)[CH3:2].[O-]CC.[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]1[N:12]2[NH:11][C:10](=[S:13])[N:9]=[C:8]2[CH:7]=[C:6]([F:14])[N:5]=1)[CH3:2]
Reactant: CCOc1nc(F)cc2n[nH]c(=S)n12
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(F)cc2nc(=S)[nH]n12

Procedure:
A mixture of 5.8 g (26 mmol) of 5-ethoxy-7-fluoro-1,2,4-triazolo[4,3-c]pyrimidine-3(2H)-thione in 50 mL of absolute ethanol was prepared and to this was added at 0° C. with vigorous stirring and cooling 12.2 mL (33 mmol) of 21 weight percent sodium ethoxide in ethanol. A mildly exothermic reaction took place and the mixture changed from a suspension to a plum colored solution. The mixture was stirred at below 10° C. for 2.25 hours to complete the reaction. It was then acidified with 25 mL of 1.25N hydrochloric acid, stirred at -10° C. for 30 min, and filtered to recover the precipitate that formed. The precipitate was washed with 10 mL of cold water and dried to obtain 3.3 g (60 percent of theory) of the title compound of 98 percent purity. A second crop amounting to 1.7 g of 60 percent purity material (19 percent of theory) was obtained from the filtrate. The title compound melts at 83.5° C. to 86.5° C. and is a white solid.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH2:16])=[O:15].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>ClCCl>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:8][N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[C:14]([NH2:16])=[O:15])=[O:23])=[CH:20][CH:19]=1
Reactant: NC(=O)c1cccn1N
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1cccn1NC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (3.10 ml, 22.4 mmol) is added to a suspension of 1-amino-1H-pyrrole-2-carboxylic acid amide (1.25 g, 10.0 mmol) in dichloromethane (13 ml). Then 4-bromo-benzoyl chloride (2.19 g, 10.0 mmol) is added slowly. The reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is washed with water and 1 N HCl. The organic phase is evaporated to give crude 1-(4-bromo-benzoylamino)-1H-pyrrole-2-carboxylic acid amide as light orange solid, which is used as such in the next reaction; HPLC/MS 1.56 min (C), [M+H] 308/310.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][C@H:35]([CH3:39])[CH2:36][NH:37][CH3:38])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][C@H:35]([CH3:39])[CH2:36][N:37]([CH3:38])[C:3](=[O:4])[C:2]([OH:1])([CH3:7])[CH3:6])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CC(C)(O)C(=O)O
Reactant: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C[C@H](CN(C)C(=O)C(C)(C)O)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 28 %

Procedure:
The procedure described in Example 1 was repeated using 2-hydroxy-iso-butyric acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1R)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 2.3, preparation of starting materials) to give the title compound as a white solid in 28% yield; NMR spectrum (DMSO-d6 373K) 1.25 (s, 3H), 1.27 (s, 3H), 1.43 (d, 3H), 3.26 (s, 3H), 3.54 (m, 1H), 4.16 (dd, 1H), 5.16 (m, 1H), 5.28 (s, 2H), 7.23 (m, 2H), 7.34 (m, 2H), 7.58 (m, 2H), 7.69 (t, 1H), 7.83 (dt, 1H), 8.07 (d, 1H), 8.46 (s, 1H), 8.58 (d, 1H), 9.88 (s, 1H); Mass spectrum MH+ 536.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][NH2:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH:13]1([CH2:18][C@H:19]([CH2:23][N:24]([CH:32]=[O:33])[O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:20](O)=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[N:5]=[C:6]([NH:9][NH:10][C:20](=[O:21])[C@H:19]([CH2:18][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:23][N:24]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:32]=[O:33])[C:7]=1[F:8]
Reactant: CSc1nc(Cl)c(F)c(NN)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A mixture of 4-chloro-5-fluoro-6-hydrazino-2-(methylthio)pyrimidine (9.70 g, 46.5 mmol), (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (19.9 g, 46.5 mmol), HOAt (6.96 g, 51.2 mmol), EDCI (9.82 g, 51.2 mmol) and N-methyl morpholine (25.6 mL, 232.5 mmol) in DMF (300 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate/hexanes (3:2, 1 L) and washed with water (3×500 mL), and the organics were dried (Na2SO4) and concentrated in vacuo. The residue was purified by Gilson RP-HPLC (35-95% acetonitrile/water, 8 min gradient time) to afford [(2R)-3-{2-[6-chloro-5-fluoro-2-(methylthio)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as a red glass (12.89 g, 56.0%). LCMS: (M+H)+: 490.4.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([O:27][C:28](=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)([CH3:26])[CH3:25]>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:28]([O:27][CH:24]([CH3:25])[CH3:26])=[O:35])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)CCCCCBr
Reactant: Oc1ccc2nc(-c3ccccc3)n(Cc3ccccc3)c2c1
Product: CC(C)OC(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(Cc3ccccc3)c2c1

Procedure:
1-Benzyl-6-hydroxy-2-phenylbenzimidazole is alkylated according to general operating instructions 2 with 6-bromo-hexanoic acid isopropyl ester. 1-Benzyl-2-phenyl-6-[(5-(iso-propyl-oxycarbonyl)pentyl]oxy]-benzimidazole is obtained as a resin.
Reaction SMILES: [O-]CC.[Na+].[Na].C([S:9][CH:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]1)(=O)C.[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18]>C(O)C>[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][S:9][CH:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]1)[CH3:18]
Reactant: CC(=O)SC1C=CCCCC1
Reactant: CCOC(CBr)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(CSC1C=CCCCC1)OCC
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A solution of fresh sodium ethoxide prepared from 7.6 g (0.330 gram-atom metallic sodium) in 200 ml of absolute ethanol was treated dropwise with 56.18 g (0.330 mole) of 3-acetylmercaptocycloheptene in 10 ml of absolute ethanol. The reaction was heated under reflux for 15 minutes and then cooled to room temperature. A solution of 49.69 ml (0.330 mole) of bromoacetaldehyde diethylacetal in 30 ml of absolute ethanol was added dropwise. The reaction mixture was heated under reflux for 2.0 hours and cooled. The precipitated sodium bromide was filtered and washed well with absolute ethanol. The filtrate was concentrated and the residue partitioned between ether/brine. The aqueous phase was further extracted with ether. The organic extracts were pooled, dried over magnesium sulfate, and evaporated to afford 80.1 g (0.328 mole, 99%) of pure 3-[(2,2-diethoxyethyl)thio]-1-cycloheptene, as a colorless oil.
Reaction SMILES: [C:1]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[K+].[CH:16](=[O:19])[CH2:17][CH3:18].C(O)(=O)C>CO>[C:1]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[C:17]([CH3:18])[CH:16]=[O:19])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC=O
Reactant: CCC(C)(C)c1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCC(C)(C)c1ccc(C=C(C)C=O)cc1
Temperature: 40 °C

Procedure:
162.2 g of p-tert.amyl-benzaldehyde are added under nitrogen gasification to a solution of 1.56 g of potassium hydroxide in 113 ml of methanol and 48.8 g of propionaldehyde are subsequently added dropwise at 40° C. over a period of 6 hours. The mixture is subsequently stirred at 40° C. for an additional hour, 2 ml of acetic acid are added and the mixture is concentrated on a rotary evaporator. The oily suspension is taken up in ether, washed neutral with water, dried and evaporated. By distillation there is obtained pure 3-(p-tert.amyl-phenyl)-2-methyl-acrolein of boiling point 117°-120° C./0.035 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[NH2:22][C:23]1[C:28]([NH2:29])=[CH:27][C:26]([N:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[CH2:35][OH:36])=[C:25]([Cl:37])[CH:24]=1.C(Cl)CCl>CC#N>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:19][C:20]1[NH:29][C:28]2[CH:27]=[C:26]([N:30]3[CH2:34][CH2:33][CH2:32][C@@H:31]3[CH2:35][OH:36])[C:25]([Cl:37])=[CH:24][C:23]=2[N:22]=1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: Nc1cc(Cl)c(N2CCC[C@@H]2CO)cc1N
Solvent: ClCCCl
Solvent: CC#N
Product: O=C(NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(N4CCC[C@@H]4CO)cc3[nH]2)c1)C1(C(F)(F)F)CC1

Procedure:
The title compound was prepared from N-(4-chloro-3-isothiocyanato-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide (85 mg, 0.3 mmol), (R)-1-(4,5-diamino-2-chloro-phenyl)-2-hydroxymethyl-pyrrolidine (62 mg, 0.3 mmol) and EDC (45 μL, 0.3 mmol) in MeCN (5 mL) in analogy with the method described in example 1 step (g).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:20]=[C:19]([F:21])[C:18]3[O:17][C:16]4[C:11](=[CH:12][C:13]([NH2:22])=[CH:14][CH:15]=4)[C@@:10]4([CH2:27][CH2:26][O:25][C:24]([NH2:28])=[N:23]4)[C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.[H][H]>CCO.[Pd]>[F:21][C:19]1[C:18]2[O:17][C:16]3[C:11](=[CH:12][C:13]([NH2:22])=[CH:14][CH:15]=3)[C@@:10]3([CH2:27][CH2:26][O:25][C:24]([NH2:28])=[N:23]3)[C:9]=2[CH:8]=[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:20]=1
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c(F)cc(C3CCOCC3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
The (S)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthene]-2,7′-diamine (0.231 g, 0.606 mmol) was taken up in EtOH (2 mL). Palladium (10%) on carbon (0.090 g, 0.084 mmol) was added. A 1-L balloon filled with hydrogen was emptied into the flask, venting through a needle. The vent was removed, and another 1-L balloon was attached. The reaction was stirred at RT overnight. The reaction was filtered through Celite, rinsing with 10% MeOH-DCM (60 mL). The filtrate was concentrated. The residue was purified through silica gel (35 mL) which had been deactivated with Et3N (3.5 mL), eluting with 4% to 8% MeOH-DCM containing 1% v/v Et3N, affording (S)-4′-fluoro-2′-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthene]-2,7′-diamine (48 mg, 0.123 mmol). MS m/z=384 [M+H]+.
Reaction SMILES: [CH:1]1([NH:9][NH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:21][C:22]([CH3:27])([CH3:26])[C:23](Br)=[O:24]>>[Br:21][C:22]([CH3:27])([CH3:26])[C:23]([N:9]([CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:24]
Reactant: CC(C)(Br)C(=O)Br
Reactant: O=C(NNC1CCCCCCC1)OCc1ccccc1
Product: CC(C)(Br)C(=O)N(NC(=O)OCc1ccccc1)C1CCCCCCC1

Procedure:
Benzyl 2-cyclooctylhydrazinecarboxylate and 2-bromoisobutyryl bromide were used for a similar reaction and treatment as Process 3 of Example 1, and benzyl 2-(2-bromoisobutyryl)-2-cyclooctylhydrazinecarboxylate was obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[NH:12][NH:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]([CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[NH:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NNC(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Reactant: O=Cc1cccnc1
Solvent: ClC(Cl)Cl
Product: O=C1NN(Cc2cccnc2)C(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(3,4-Dichloro-phenyl)-5-pyridin-4-yl-pyrazolidin-3-one 0.30 g and 0.12 mL 3-pyridinecarboxaldehyde in chloroform 20 mL was added NaBH3(CN) 0.1 g at 0° C., the reaction was warmed 50° C. and stirred for 1 hour. The reaction was quenched with sat.NaHCO3 25 mL at 0° C. The reaction mixture was extracted with dichloromethane, 3×50 mL. The combined organic phase was washed with brine, dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained as yellow solid 0.28 g. MS (ES+): 399 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.ClC1C=CC=C(C(OO)=O)C=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=1)=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClCCCCSCc1ccc2nccn2c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=S(CCCCCl)Cc1ccc2nccn2c1
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
11.79 g of the 6-((4-chlorobutyl)thiomethyl)-imidazo[1,2-a]pyridine prepared in the Preparative Example 7 was dissolved in 160 ml of dichloromethane. The obtained solution was cooled with ice, followed by the addition of 7.99 g of m-chloroperbenzoic acid in about 40 minutes. The obtained mixture was stirred. After 30 minutes, 0.4 g of m-chloroperbenzoic acid was further added thereto. The obtained mixture was additionally stirred for one hour, followed by the addition of an aqueous solution of sodium thiosulfate. The obtained mixture was vigorously stirred at room temperature for 30 minutes and extracted with chloroform. The organic phase was washed with an aqueous solution of potassium carbonate, dried over anhydrous magnesium sulfate, and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (30:1 to 10:1)] to give 9.51 g of the title compound as a dark-creamy oil (yield: 78%).