Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([O:11][C:12]([N:14]1[C:23]2[C:18](=[N:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[C@H:17]([N:28]([CH2:44][C:45]2[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[C:47]([C:55]([F:58])([F:57])[F:56])[CH:46]=2)[C:29]2[N:30]=[N:31][N:32]([CH2:34][CH2:35][NH:36]C(OC(C)(C)C)=O)[N:33]=2)[CH2:16][C@@H:15]1[CH2:59][CH3:60])=[O:13])([CH3:10])[CH3:9].C(=O)(O)[O-].[Na+]>ClCCl>[CH:8]([O:11][C:12]([N:14]1[C:23]2[C:18](=[N:19][C:20]([C:24]([F:27])([F:25])[F:26])=[CH:21][CH:22]=2)[C@H:17]([N:28]([C:29]2[N:30]=[N:31][N:32]([CH2:34][CH2:35][NH2:36])[N:33]=2)[CH2:44][C:45]2[CH:46]=[C:47]([C:55]([F:56])([F:57])[F:58])[CH:48]=[C:49]([C:51]([F:52])([F:53])[F:54])[CH:50]=2)[CH2:16][C@@H:15]1[CH2:59][CH3:60])=[O:13])([CH3:10])[CH3:9]
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCNC(=O)OC(C)(C)C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCN)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
Add trifluoroacetic acid (1 mL) to a solution of (+/−)-cis-4-[(3,5-bis-trifluoromethyl-benzyl)-[2-(2-tert-butoxycarbonylamino-ethyl)-2H-tetrazol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (61 mg, 0.079 mmol) in dichloromethane (3 mL) and stir the mixture at room temperature for 3 h. Pour the reaction mixture onto a saturated solution of sodium bicarbonate and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by silica gel chromatography, eluting with ethyl acetate, to afford the title compound (24 mg, 45%). MS (ES+): 669 (M+H).
Reaction SMILES: O=[C:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7].Cl.[NH2:10][OH:11].C(=O)([O-])[O-].[Na+].[Na+]>>[N:10](=[C:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7])[OH:11]
Reactant: CC(=O)CCCC#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(CCCC#N)=NO

Procedure:
Chem. Ber. 1966, 3387 to 3389 discloses the preparation of 1,5-diaminohexane from 5-oxocapronitrile. In this process, 1,5-diaminohexane is only obtained via the oxime intermediate by first reacting 5-oxocapronitrile with hydroxylamine hydrochloride in the presence of anhydrous sodium carbonate to give 5-oximinocapronitrile, which is subsequently reacted with lithium aluminum hydride to give the diamine; the overall yield is 42%. According to the authors, direct reductive amination of 5-oxocapronitrile gives the cyclization product, 2-methylpiperidine.
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=[N:55][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CCCC1>CN(C=O)C>[CH:50]1([NH:55][C:30](=[O:31])[C:29]2[CH:33]=[C:34]([F:37])[C:35]([CH3:36])=[C:27]([C:10]3[C:11]4[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]5[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=5[F:26])[C:12]=4[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:38][CH3:39])[N:9]=3)[CH:28]=2)[CH2:51][CH2:52][CH2:53][CH2:54]1
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC3CCCC3)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and cyclopentanamine (8.15 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (18.2 mg, 56%). LC-MS m/z 607 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][O:15]C(=O)C)[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[I:8].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C.O>CO.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: CC(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Yield: 86.2 %

Procedure:
Acetic acid (5R)-3-(3-fluoro-4-iodophenyl)-1,3-oxazolidin-2-one-5-ylmethyl ester (30 g, 79 mM) was treated with potassium carbonate (16.4 g, 0.119 mM) in a mixture of methanol (800 mL) and dichloromethane (240 mL) at ambient temperature for 25 minutes, then immediately neutralised by the addition of acetic acid (10 mL) and water (500 mL). The precipitate was filtered, washed with water, and dissolved in dichloromethane (1.2 L), the solution washed with saturated sodium bicarbonate, and dried (magnesium sulfate). Filtration and evaporation gave the desired product (23 g).
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[OH:22][CH:21]([C:20]1[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=1)[C:3]#[C:2][C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[O:4]
Reactant: C#CC(=O)OCC=C(C)C
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C(O)C#CC(=O)OCC=C(C)C)cc(OC)c1OC
Reaction time: 0.17 h

Procedure:
A solution of 6.6 g (4g mmol) of 3-methyl-2-butenyl propiolate in 60 ml of tetrahydrofuran was treated at -78° under argon with 30 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 9.4 g (48 mmol) of 3,4,5-trimethoxybenzaldehyde in 80 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 1 hour, then brought to room temperature and treated with 120 ml of saturated ammonium chloride solution The aqueous phase was extracted twice with ether. The organic phases were washed in succession with saturated sodium chloride solution and with water dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 700 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained 3-methyl-2-butenyl 4-hydroxy-4-(3,4,5-trimethoxyphenyl)-2-butynoate as a yellow oil.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[C:22]=1[Br:27]>>[Br:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[NH:20][S:2]([C:5]1[S:6][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(-c2cccc3ccccc23)s1
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3cccc4ccccc34)s2)c1Br
Yield: 22.4 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(1-napthyl)thiophene-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-chlorosulfonyl-5-(1-napthyl)thiophene (200 mg, 0.65 mmol) with 5-amino-4-bromo-3-methylisoxazole (0.65 mmol), after purification by column chromatography using 1% MeOH/CHCl3, gave 65.3 mg of pure N-(4-bromo-3-methyl-5-isoxazolyl)-5-(1-napthyl)thiophene-sulfonamide as a brown solid, (22% yield, m.p. 118° C.).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[NH:10][C:9]=2[C:8]([OH:21])=[CH:7][CH:6]=1)=[O:4].O[Li].O>C1COCC1.CO.O>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[NH:10][C:9]3[C:8]([OH:21])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3)nc12
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Wang resin-supported 2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF, LiOH.H2O (99 mg, 2.35 mmol) in MeOH—H2O (2:1) was added thereto and the resulting mixture was refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH2Cl2, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH2:10][OH:11].C(N(C(C)C)CC)(C)C.Cl[CH2:22][O:23][CH3:24]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH2:10][O:11][CH2:22][O:23][CH3:24]
Reactant: COCCl
Reactant: OC/C=C/c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC/C=C/c1ccccc1Cl
Temperature: 0 °C
Yield: 92.2 %

Procedure:
To a 250 ml round-bottomed flask, (E)-3-(2-chlorophenyl)prop-2-en-1-ol (2.96 g, 17.5 mmol, Preparation example 1) and Dichloromethane (17.5 ml) were added and the reaction mixture was cooled to 0° C. Diisopropylethylamine (6.1 ml, 35.1 mmol) was added and stirred at 0° C. Methyl chloromethyl ether (2.77 ml, 35.1 mmol) was added dropwise and stirred for overnight. The reaction mixture was quenched with 1N NaOH solution, extracted by dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated under vacuum. The crude compound was purified by a silica gel column to produce the title compound (3.43 g, 85˜95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)#[CH:24].C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:24]#[C:23][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: C#Cc1ccccn1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc2n1-c1sc(C#Cc3ccccn3)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was obtained by coupling 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with 2-ethynylpyridine under the conditions used in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The fractions homogenous by TLC were combined and evaporated. Crystallization of the residue from ethyl acetate and recrystallization from tetrahydrofuran/methanol gave off-white crystals of 4-(2-chlorophenyl)-9-methyl-2-[2-(2-pyridinyl)-ethynyl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with m.p. 153°-155°.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].[OH-].[K+]>O>[F:1][C:2]([F:15])([F:16])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccccc1OCC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccccc1OCC(F)(F)F

Procedure:
Methyl 2-(2,2,2-trifluoroethoxy)benzoate (8 g., 34.2 mmoles) potassium hydroxide (3.3 g., 350 mmoles), water (50 ml.) and alcohol (25 ml.) are heated together under reflux for 1.5 hours, and distilled until ca. 25 ml. of distillate is removed. The cooled residue is acidified (pH 3) and the resulting white solid is collected and recrystallized (aqueous alcohol) to give fluffy white solid, m.p. 85°-86.5° C.
Reaction SMILES: [CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]([C:15]([OH:17])=[O:16])[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21]O>S(Cl)(Cl)=O.C1C=CC=CC=1>[CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]([C:15]([O:17][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])=[O:16])[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)CCO
Reactant: O=C(O)C1Sc2ccccc2-c2ccccc21
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CN(C)CCOC(=O)C1Sc2ccccc2-c2ccccc21
Yield: 70 %

Procedure:
6H-dibenzo[b,d]thiopyran-6-carboxylic acid (3.4 g; 0.014 mol) was suspended in thionyl chloride (30 ml) and after 20 hours at room temperature the solution was evaporated in vacuo. The crude residue was dissolved in 80 ml of benzene and the obtained solution was added dropwise, at room temperature, to a solution of 2-dimethylaminoethanol (42 ml; 0.042 mol) in 80 ml of benzene. After half an hour the solution was washed with water and dried over sodium sulfate and concentrated to dryness. 6H-dibenzo[b,d]thiopyran-6-carboxylic acid, 2-dimethylamino-ethyl ester was obtained as oil; (3.0 g; yield 70%); NMR (CDCl3) δ ppm: 2.12 (s) (6H,CH3), 2.37 (t) (2H, --CH2NMe2), 4.07 (t) (2H, COOCH2), 4.59 (s) (1H,C-6 proton), 7.1-7.5 (m) (6H; C-2, C-3, C-4, C-7, C-8 and C-9 phenyl protons), 7.78 (m) (2H; C-1 and C-10 phenyl protons). By proceeding analogously the following compounds were obtained:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][O:16][S:28]([CH3:27])(=[O:30])=[O:29])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1sc2cc(C#CCCCO)ccc2c1-c1ccc(C(F)(F)F)cc1
Product: Cc1sc2cc(C#CCCCOS(C)(=O)=O)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 21.1, the 5-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol was treated with methanesulfonic acid chloride to yield the Methanesulfonic acid 5-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl ester as yellow oil, MS: 452 (M+).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:32]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Cl:32][C:23]1[CH:22]=[C:21]([CH:13]([C:10]2[CH:9]=[CH:8][C:7]([S:4]([CH:1]3[CH2:2][CH2:3]3)(=[O:6])=[O:5])=[CH:12][CH:11]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[NH:25][C:24]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1)C1CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2cc(Cl)c(-c3ccccn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
To a solution of 2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (200 mg) in tetrahydrofuran (5 mL) was added N-chlorosuccinimide (61.2 mg) at 0° C., and the mixture was stirred overnight at room temperature, and further at 50° C. for 1 day. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (60.0 mg, yield 28%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 471 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[NH:4][C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:22])[NH:20][CH3:21])[CH:14]=3)[CH:10]=[N:9][N:8]2[CH:23]=1.C1C(=O)N([Br:32])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:24])[NH:4][C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:22])[NH:20][CH3:21])[CH:14]=3)[CH:10]=[N:9][N:8]2[C:23]=1[Br:32]
Reactant: O=C1CCC(=O)N1Br
Reactant: CNC(=O)c1cccc(-c2cnn3cc(NC(=O)OC)nc3c2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(-c2cnn3c(Br)c(NC(=O)OC)nc3c2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
[7-(3-Methylcarbamoyl-phenyl)-imidazo-[1,2-b]-pyridazin-2-yl]-carbamic acid methyl ester (1 eq, 0.167 mmol, 55 mg) is dissolved in DMF (1 ml) at 0° C. and NBS (1.1 eq, 0.184 mmol, 33.8 mg) is added. The reaction mixture is stirred for 1 h at 0° C. and then is diluted with EtOAc. The reaction is washed with NaHCO3 and brine, dried over MgSO4, filtered and evaporated to yield [3-Bromo-7-(3-Methylcarbamoyl-phenyl)-imidazo-[1,2-b]-pyridazin-2-yl]-carbamic acid methyl ester as a brown solid which did not require further purification; [M+H]+=406
Reaction SMILES: C(OC(=O)CCNC(=O)C1C=CC(CN)=CC=1)C.C1C2(CCCCC2)CCC(=O)C1.[CH2:31]([O:33][C:34](=[O:59])[CH2:35][CH2:36][NH:37][C:38](=[O:58])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][NH:46][CH:47]2[CH2:52][CH2:51][C:50]3([CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]3)[CH2:49][CH2:48]2)=[CH:41][CH:40]=1)[CH3:32].C(N(C(C)C)CC)(C)C.[F:69][C:70]1[CH:71]=[C:72]([CH:76]=[C:77]([C:79]([F:82])([F:81])[F:80])[CH:78]=1)[C:73](Cl)=[O:74]>C(#N)C>[CH2:31]([O:33][C:34](=[O:59])[CH2:35][CH2:36][NH:37][C:38](=[O:58])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][NH:46][CH:47]2[CH2:52][CH2:51][C:50]3([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]3)[CH2:49][CH2:48]2)=[CH:41][CH:40]=1)[CH3:32].[CH2:31]([O:33][C:34](=[O:59])[CH2:35][CH2:36][NH:37][C:38](=[O:58])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][N:46]([C:73](=[O:74])[C:72]2[CH:76]=[C:77]([C:79]([F:80])([F:81])[F:82])[CH:78]=[C:70]([F:69])[CH:71]=2)[CH:47]2[CH2:52][CH2:51][C:50]3([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]3)[CH2:49][CH2:48]2)=[CH:41][CH:40]=1)[CH3:32]
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Agent: CCOC(=O)CCNC(=O)c1ccc(CN)cc1
Agent: CCOC(=O)CCNC(=O)c1ccc(CNC2CCC3(CCCCC3)CC2)cc1
Agent: O=C1CCC2(CCCCC2)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1ccc(CN(C(=O)c2cc(F)cc(C(F)(F)F)c2)C2CCC3(CCCCC3)CC2)cc1
Reaction time: 1 h
Yield: 200.2 %

Procedure:
3-[4-(Spiro[5.5]undec-3-ylaminomethyl)benzoylamino]propionic acid ethyl ester was prepared by reductive alkylation of 3-(4-aminomethyl-benzoylamino)propionic acid ethyl ester with spiro[5.5]undecan-3-one. 3-[4-(Spiro[5.5]undec-3-ylaminomethyl)benzoylamino]propionic acid ethyl ester (200 mg, 499 μmol) was dissolved in acetonitrile (5 mL) and diisopropylethylamine (170 μL) and cooled on an ice bath. Commercially available 3-fluoro-5-(trifluoromethyl)benzoylchloride (136 mg, 602 μmol) dissolved in acetonitrile (5 mL) was added dropwise. The reaction was complete within one hour as shown by HPLC. The solvent was evaporated and water (10 mL) was added to the residue followed by saturated sodium bicarbonate (10 mL). The product was extracted using ethyl acetate (2×50 mL). The combined ethyl acetate extracts were washed with water (20 mL) and brine (20 mL). Drying the organic phases over MgSO4 and evaporation of the solvent afforded 3-(4-{[(3-fluoro-5-trifluoromethylbenzoyl)spiro[5.5]undec-3-yl-amino]methyl}benzoylamino)propionic acid ethyl ester (295 mg) which was hydrolyzed using sodium hydroxide to afford the title compound.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(SCc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 2 from 8-benzylthio-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 188°-190° C.) and piperazine.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([NH:12][NH2:13])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].[CH3:24][N:25]=[C:26]=S.C(O)C>CN(C=O)C>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:24]([NH:25][CH3:26])=[N:13][NH:12][C:8]=2[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CN=C=S
Reactant: CCCCn1c(=O)cc(NN)n(Cc2ccc(OC)cc2)c1=O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc(OC)cc2)c1=O
Yield: 53 %

Procedure:
A solution of 3-butyl-6-hydrazino-1-(4-methoxybenzyl)-uracil (2.0 g, 6.3 mM) and methyl isothiocyanate (1.36 ml, 20 mM) in DMF (20 ml) was stirred at 120° C. for 20 hours. To the solution was added ethanol (20 ml) and the mixture was cooled to give crude crystals. Recrystallization from DMF/ethanol gave colorless crystals (1.2 g, 53%), m.p. 292°-294° C.
Reaction SMILES: [CH3:1][Al](C)C.[Si:5]([O:12][C@H:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:16]([CH:26]=O)[CH2:15][CH2:14]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]>C1COCC1.ICI.C(OCC)(=O)C.[Zn]>[Si:5]([O:12][C@H:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[C@@H:16]([CH:26]=[CH2:1])[CH2:15][CH2:14]1)([C:8]([CH3:11])([CH3:9])[CH3:10])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1C=O
Reactant: C[Al](C)C
Agent: [Zn]
Solvent: C1CCOC1
Solvent: ICI
Solvent: CCOC(C)=O
Product: C=C[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a suspension of zinc dust (12.2 g) in THF (200 mL) and diiodomethane (5 mL) at 0° C. was added trimethylaluminium (2M in hexanes, 6 mL). After the addition the reaction was carefully warmed to room temperature (exothermic reaction!). The reaction was then cooled with an ice bath and a solution of tert-butyl (2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-formylpiperidine-1-carboxylate (Intermediate 189, 6.84 g) in THF (40 mL) was added. After 6 hours it was warmed to room temperature, the reaction was diluted with ethyl acetate and slowly quenched with a saturated aqueous solution of NaHCO3. The organic phase was collected and washed with NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. Chromatography on silica gel with a gradient of 0-100% methylene chloride in hexanes gave 3.96 g of product.
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].[C:6]([O:9][C@:10]1([C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH2:27][CH2:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1)[C:11](=[O:17])[CH2:12][O:13][C:14](=[O:16])[CH3:15])(=[O:8])[CH3:7]>C(Cl)Cl.COCOC.P(Cl)(Cl)(Cl)=O.O>[C:6]([O:9][C@:10]1([C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH2:27][CH2:28]2)[C:23](=[CH2:1])[CH2:22]3)[CH2:19][CH2:18]1)[C:11](=[O:17])[CH2:12][O:13][C:14](=[O:16])[CH3:15])(=[O:8])[CH3:7]
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: COCOC
Solvent: O=P(Cl)(Cl)Cl
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(OC(C)=O)C(=O)COC(C)=O)[C@@]2(C)CCC(=O)C=C12
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A suspension of 1.0 g of sodium acetate in 30 ml of methylene chloride, 30 ml of formaldehyde dimethylacetal and 3.8 ml of phosphorus oxychloride is combined with 1.0 g of 17,21-diacetoxy-4-pregnene-3,20-dione and refluxed for 35 hours under agitation. After cooling to room temperature, the mixture is diluted with methylene chloride and water. Under stirring, a saturated soda solution is added dropwise until an alkaline reaction of the aqueous phase has been obtained. The organic phase is separated, washed with water, dried over sodium sulfate, and evaporated under vacuum. Finally, the product is recrystallized from acetone/hexane, thus isolating 825 mg of 17,21-diacetoxy-6-methylene-4-pregnene-3,20-dione, mp 227°-228° C.