Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:17][CH:18]=2)[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].C([O-])([O-])=O.[Ca+2].[C:30](Cl)(Cl)=[S:31]>O>[N:13]([C@H:12]([C:14]1[N:15]=[C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[S:17][CH:18]=1)[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=1)=[C:30]=[S:31]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2ccccc2)n1
Reactant: S=C(Cl)Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=[N+]([O-])c1ccc(C[C@H](N=C=S)c2csc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To a solution of (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine hydrobromide salt, 38, (2.03 g, 5 mmol) and CaCO3 (1 g, 10 mmol) in CC4/water (10:7.5 mL) is added thiophosgene (0.46 mL, 6 mmol). The reaction is stirred at room temperature for 18 hours then diluted with CH2C2 and water. The layers are separated and the aqueous layer extracted with CH2Cl2. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated in vacuo to a residue that is purified over silica (CH2Cl2) to afford 1.71 g (93% yield) of the desired product. ESI+ MS 368 (M+1).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:32]#[N:33])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][C:26]([N:28]([CH3:30])[CH3:29])=[N:25][C:24]=3[CH:31]=1)[CH:12]=2)=[O:7])CCC.[NH2:34][CH2:35][C:36]([OH:38])=[O:37].C[O-].[Na+].CO>>[C:32]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([N:28]([CH3:30])[CH3:29])=[N:25][C:24]=4[CH:31]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:7])[N:9]=1)#[N:33]
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc4oc(N(C)C)nc4c3)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)c1nc2cc(Oc3ccc4c(O)c(C(=O)NCC(=O)O)nc(C#N)c4c3)ccc2o1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
A mixture of 1-cyano-7-(2-dimethylamino-benzooxazol-5-yloxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (37 mg, 0.08 mmol), glycine (126 mg, 1.68 mmol) and 0.5 M sodium methoxide/methanol (3.2 mL) was refluxed for twenty-five hours before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (20 mL) and extracted with dichloromethane (2×25 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (2.4 mL). The white precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (24 mg): MS: (+) m/z 448.27 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])[CH2:14][C:13]2[C:8](=[C:9]([O:21][CH3:22])[C:10]([O:19][CH3:20])=[C:11]([O:17][CH3:18])[C:12]=2[O:15][CH3:16])[CH2:7]1)=[O:5])[CH3:2].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:31])[CH2:7][C:8]2[C:13](=[C:12]([O:15][CH3:16])[C:11]([O:17][CH3:18])=[C:10]([O:19][CH3:20])[C:9]=2[O:21][CH3:22])[CH2:14]1)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)C1(CCCCCCCC(=O)O)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(CCCCCCCC(=O)N2CCOCC2)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.6 %

Procedure:
A THF (4.0 ml) suspension of 8-(2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl)octanoic acid (114 mg, 0.252 mmols), morpholine (0.110 ml, 1.26 mmols), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96.6 mg, 0.504 mmols) and 1-hydroxybenzotriazole monohydrate (77.2 mg, 0.504 mmols) was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, to which was added water. Then, this was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:1) to obtain the entitled compound (123 mg) as an oil.
Reaction SMILES: C1(S([C:10]2[CH:25]=[CH:24][C:13]3[N:14]([C:18](=O)[CH2:19][CH2:20][NH:21][CH3:22])[CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=O)=O)C=CC=CC=1.B.Cl.Cl.[C:29]1([S:35](C2C=CC3N(CCCNC)CCOC=3C=2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)C.C1COCC1>[C:29]1([S:35]([C:25]2[CH:10]=[CH:11][C:12]3[O:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][NH:21][CH3:22])[C:13]=3[CH:24]=2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CNCCC(=O)N1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: CNCCCN1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: B
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNCCCN1CCOc2ccc(S(=O)(=O)c3ccccc3)cc21
Temperature: 0 °C

Procedure:
To 1 mL of freshly distilled THF was added 1-(7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-3-methylamino-propan-1-one (0.075 g, 0.210 mmol) and the resulting solution was cooled to 0° C. Borane:THF complex (0.315 mL of a 1 M solution, 0.315 mmol) was added dropwise over 2 minutes, during which offgassing was observed. The solution was warmed to reflux for 6 hours with stirring and then cooled to room temperature. Ethanolic hydrogen chloride (0.750 mL of a 2N solution, 1.5 mmol) was added dropwise accompanied by vigorous offgassing. The reaction mixture was refluxed for 2 hours at which time a white solid was observed in the solution. To the reaction mixture was added 2 mL diethyl ether and the solid was filtered and dried overnight under reduced pressure to give 0.045 g. of [3-(7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propyl]-methyl-amine hydrochloride as a fluffy white solid. MS: 347 (M+H)+, mp: 188.3-193.2° C. (as hydrochloride salt).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:7](=[O:16])[C@H:6]1[NH2:17])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[C:1]([O:4][C@@H:5]1[N:8]([Si:9]([C:12]([CH3:13])([CH3:15])[CH3:14])([CH3:10])[CH3:11])[C:7](=[O:16])[C@H:6]1[NH:17][C:32](=[O:33])[CH2:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](N)C(=O)N1[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1[Si](C)(C)C(C)(C)C
Yield: 90.6 %

Procedure:
To a solution of 0.387 g of (3S,4S)-4-acetoxy-3-amino-1-t-butyldimethylsilyl-2-oxoazetidine in 20 ml of THF is added 0.24 g of triethylamine under ice-cooling, and then, a solution of 0.32 g of phenylacetyl chloride in THF is added dropwise. The mixture is stirred under ice-cooling for one hour, the insolubles are filtered off, and the filtrate is concentrated under reduced pressure. Purifying the residue on a silica gel column (ethyl acetate:n-hexane=1:2) yields 0.511 g of (3S,4S)-4-acetoxy-1-t-butyldimethylsilyl-3-phenylacetamido-2-oxoazetidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([OH:20])[CH:11]=2)=[CH:4][N:3]=1.[CH2:21](C(O)=O)[C@H:22](O)[C:23](O)=[O:24].[OH-].[NH4+]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:11]3[CH:21]=[CH:22][C:23](=[O:24])[O:20][C:12]=3[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][N:3]=1
Reactant: O=C(O)C[C@H](O)C(=O)O
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(O)c1OC
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc(Cc2cnc(N)nc2N)c2ccc(=O)oc2c1OC
Temperature: 0 °C

Procedure:
A mixture of 1.38 g (0.005 mole) of 2,4-diamino-5-(3-hydroxy-4,5-dimethoxybenzyl)pyrimidine and 1.01 g (0.0075 mole) of L-(-)-malic acid in polyphosphoric acid (30 g) was heated at 90°-100° for 4 hours. The resulting clear syrup was poured into ice-water (150 mL) and basified (pH 8) with conc'd ammonium hydroxide. The title compound was filtered off and washed with ethanol. Yield, 0.26 g (16%); m.p. 278°-280° dec; structure confirmed by 13C and 1H NMR and mass spectra. Anal. Calcd. for C16H18N4O3 : C, 58.53; H, 4.91; N, 17.07. Found: C, 58.27; H, 4.99; N, 16.97.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([O:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:10]=2[N:11]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:30]=[N:31][CH:32]=2)O1.C([O-])(O)=O.[Na+]>O1CCOCC1>[O:16]1[CH2:17][CH2:18][CH:13]([O:12][C:9]2[C:10]3[N:11]=[C:2]([C:27]4[CH:28]=[C:29]([NH:33][S:34]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)(=[O:35])=[O:36])[CH:30]=[N:31][CH:32]=4)[CH:3]=[CH:4][C:5]=3[N:6]=[CH:7][N:8]=2)[CH2:14][CH2:15]1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccccc1
Temperature: 25 °C
Yield: 19.1 %

Procedure:
To a solution of 6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine (Intermediate 1) (60.0 mg, 0.226 mmol) in 1,4-dioxane (1.20 mL) was added N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (Intermediate 2) (122 mg, 0.339 mmol), PdCl2(dppf)2CH2Cl2 (18.0 mg, 0.0230 mmol), and 1N aq. NaHCO3 (0.452 mL, 0.452 mmol) at room temperature. The reaction mixture was subjected to microwave irradiation for 30 min at 120° C., and cooled to room temperature. The reaction mixture was filtered through a Celite pad and washed with EtOAc. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=3:1) to give N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide (20.0 mg, 19%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.02-2.11 (2H, m), 2.23-2.27 (2H, m), 3.68-3.74 (2H, m), 4.10-4.15 (2H, m), 5.64-5.69 (1H, m), 7.07 (1H, brs), 7.47-7.51 (2H, m), 7.56-7.60 (1H, m), 7.85-7.88 (2H, m), 8.21 (1H, d, J=8.8 Hz), 8.36 (1H, d, J=8.8 Hz), 8.38 (1H, s), 8.43 (1H, t, J=2.2 Hz), 8.83 (1H, s), 9.16 (1H, s); m/z=464.2 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[C:15]([OH:19])([CH3:18])([CH3:17])[CH3:16]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12]
Reactant: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: CC(C)(C)O
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C

Procedure:
Using the procedure of Example 3, 2.7 g of (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid chloride in 12.5 ml of benzene and 1.23 ml of tert.-butanol were reacted to obtain 1.05 g of tert.-butyl (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate melting at 67° C. with a specific rotation of [α]D20 =+75.5°±2° (c=0.5% in chloroform).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](NCCN2CCCCC2)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][OH:25]>>[Cl:8][C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([O:25][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)[N:5]=1
Reactant: OCc1ccccn1
Reactant: Clc1nc(Cl)nc(NCCN2CCCCC2)n1
Product: Clc1nc(Cl)nc(OCc2ccccn2)n1

Procedure:
Following the general procedure A-2, 4,6-dichloro-N-(2-(piperidin-1-yl)ethyl)-1,3,5-triazin-2-amine was coupled with 2-pyridinemethanol with reaction time of 3 h. Purification by column chromatography gave the title compound.
Reaction SMILES: [Na].[Cl:2][S:3]([OH:6])(=O)=[O:4].[OH:7][C:8]1[CH:17]=[CH:16][C:15]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[S:29]([CH3:32])(=[O:31])=[O:30])=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](S([O-])(=O)=O)=[CH:13]2.[Na+]>>[OH:7][C:8]1[CH:17]=[CH:16][C:15]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[S:29]([CH3:32])(=[O:30])=[O:31])=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12]([S:3]([Cl:2])(=[O:6])=[O:4])=[CH:13]2
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])ccc1N=Nc1ccc(O)c2ccc(S(=O)(=O)[O-])cc12
Reactant: O=S(=O)(O)Cl
Agent: [Na+]
Agent: [Na]
Product: CS(=O)(=O)c1cc([N+](=O)[O-])ccc1N=Nc1ccc(O)c2ccc(S(=O)(=O)Cl)cc12

Procedure:
The 5-hydroxy-8-(2-methylsulfonyl-4-nitrophenylazo)-2-naphthalenesulfonyl chloride was prepared from the sodium salt of the acid with chlorosulfonic acid; 3.55 g. (0.0075 mol) of sodium 5-hydroxy-8-(2-methylsulfonyl-4-nitrophenylazo)-2-napthalenesulfonate in 35 ml. of chlorosulfonic acid was heated at 60°C. for one hour. The solution was cooled and poured onto ice. The solid was collected on a filter funnel and dried in a vaccum desiccator to yield 2.8 g. (80 percent) of the product which contained a small amount of starting material.
Reaction SMILES: Cl.[NH2:2]O.[CH2:4]([O:6][C:7](=[O:36])[C:8](O)=[CH:9][C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:14][C:13]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:11])[CH3:5]>C(O)C>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:11][N:2]=1)=[O:36])[CH3:5]
Reactant: CCOC(=O)C(O)=CC(=O)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 25 °C

Procedure:
Hydroxylamine hydrochloride (0.89 g; 12.8 mmol) was added to a suspension of 4-(2,4-bis-benzyloxy-5-chlorophenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester (5.00 g; 10.7 mmol) in absolute ethanol (100 ml). The reaction mixture was heated at reflux for four hours then allowed to cool to ambient temperature (during this time the mixture remains heterogeneous but becomes lighter yellow in colour). The mixture was filtered and the filtered solid was washed with water (2×20 ml), ethanol (2×20 ml) and dried in vacuo at 45° C. This affords 5-(2,4-bis-benzyloxy-5-chlorophenyl)-isoxazole-3-carboxylic acid ethyl ester as a fluffy yellow solid, 4.49 g (91%) LCMS: [M+H]+ 466, 464 (37Cl; 35Cl)). 1H NMR (400 MHz, CDCl3) δ 1.42 (t, 3H), 4.42 (q, 2H), 5.13 (s, 2H), 5.14 (s, 2H), 6.62 (s, 1H), 7.01 (s, 1H), 7.35-7.43 (m, 10H), 8.00 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1/[C:9](=[N:11]/[S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])/[CH3:10].Br[C:19]([F:26])([F:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH3:17][C:14]([CH3:15])([S@:12]([NH:11][C@@:9]([C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[F:1])([CH3:10])[C:19]([F:26])([F:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:13])[CH3:16]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1cc(Br)ccc1F
Product: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1cc(Br)ccc1F

Procedure:
Starting from (R)-2-methyl-propane-2-sulfinic acid [1-(2-fluoro-5-bromo-phenyl)-(E)-ethylidene]-amide and ethyl 2-bromo-2,2-difluoroacetate, the product (3R)-ethyl 3-((R)-1,1-dimethyl ethyl sulfinamido)-2,2-difluoro-3-(2-fluoro-5-bromo-phenyl)butanoate was obtained as an orange oil. MS (ISP): m/z=446.1 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2C[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:6]=2[C:5]=1[C:15]([O:17]C)=O)=[C:2]=[S:3].[CH3:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=1>>[CH3:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][CH2:26][CH2:27][N:28]2[C:15](=[O:17])[C:5]3[C:6]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:24]=1
Reactant: COC(=O)c1c(N=C=S)sc2c1CCCCCC2
Reactant: Cc1cn(CCCN)cn1
Product: Cc1cn(CCCn2c(=S)[nH]c3sc4c(c3c2=O)CCCCC4)cn1

Procedure:
The compound was synthesized starting from methyl 4,5,6,7,8,9-hexahydro-2-isothiocyanatocycloocta[b]thiophene-3-carboxylate (0.100 g. 0.36 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.049 g, 0.36 mmol) as described above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[S:11].[C:16]([O-])([O-])=O.[K+].[K+].O.CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:15])[CH3:14])[S:11][CH3:16]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: CSC(=NC(C)=O)Nc1c(Cl)cccc1Cl
Reaction time: 5 h

Procedure:
26.3 g (0.1M) of N-(2,6-dichlorophenyl)-N'-acetylthiourea, 9.9 g (0.06M) of ground 2 K2CO3.3 H2O, 8.3 ml (0.13M) of methyliodide and 200 ml of acetone are put to boil and are energetically shaken for 5 hours. The acetone is distilled off and the residue is washed with water and filtered. The sediment on the filter is washed once or twice more with water. After drying the product is boiled in a reflux with isopropanol 1:6, weight:volume) and is filtered. From the filtrate 22.0 g of N-(2,6-dichloro-phenyl)-N'-acetyl-S-methylisothiourea (79.4% of the theoretical yield), melting point 137° to 140° C. are isolated.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[CH:5]([C:7]1[N:16]=[C:15]([OH:17])[C:14]2[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11][CH2:10][C:9]=2[N:8]=1)[CH3:6].ClC(C)C#N>>[CH3:1][N:2]([CH3:3])[CH:5]([C:7]1[N:16]=[C:15]([OH:17])[C:14]2[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11][CH2:10][C:9]=2[N:8]=1)[CH3:6]
Reactant: CC(Cl)c1nc(O)c2c(n1)CCC(C)(C)C2
Reactant: CNC
Agent: CC(Cl)C#N
Product: CC(c1nc(O)c2c(n1)CCC(C)(C)C2)N(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of dimethylamine (2M solution in tetrahydrofuran, 4.0 mL, 8.0 mmol) was added 2-(1-chloroethyl)-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-ol (synthesized according to the method of reagent preparation 18 using 2-chloropropionitrile in step 1) (50 mg, 0.21 mmol) and the reaction mixture was stirred in a sealed tube for 16 hours at 80° C. After cooling to room temperature the reaction mixture was concentrated and the residue was partitioned between brine (50 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to give 2-[1-(dimethylamino)ethyl]-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-ol (50 mg, 96%). MS (EI) for C14H23N3O: 250 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:36])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([CH:34]=4)=[CH:32][C:31]([CH3:35])=[CH:30][CH:29]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:38].[ClH:40].CCOCC>>[ClH:38].[ClH:40].[ClH:38].[CH3:35][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[N:26][C:25]([C:23]1[C:22]([NH2:36])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:18]=3)[CH:24]=1)=[CH:34]2
Reactant: Cc1ccc2cnc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)cc2c1
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Product: Cc1ccc2cnc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)cc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-{4-[6-amino-5-(6-methylisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (29.5 mg, 0.0609 mmol) in DCM (1.0 mL, 16 mmol) was added 1.0 M of HCl in Et2O (1.7 mL, 1.7 mmol), and the mixture was stirred at ambient temperature for 6 h. Almost immediately a yellow solid precipitated. The solvents were evaporated, and the residue was transferred into a vial and dried in vacuo overnight to give the title compound as yellow solid. It appeared to be slightly hygroscopic. 1H NMR (400 MHz, DMSO-d6): δ=14.7 (very brs, 1H), 9.41 (s, 1H), 9.26-9.17 (brm, 1H), 9.14-9.02 (brm, 1H), 8.83 (d, J=2.0 Hz, 1H), 8.79 (brs, 1H), 8.62 (s, 1H), 8.51 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 8.15 (d, J=0.4 Hz, 1H), 7.87 (s, 1H), 7.66 (dd, J=1.2, 8.4 Hz, 1H), 7.36 (s, 1H), 7.23 (s, 1H), 7.10 (s, 1H), 4.58-4.49 (mc, 1H), 3.40 (brd, J=12.4 Hz, 2H), 3.11 (brq, J=11.8 Hz, 2H), 2.58 (s, 3H), 2.31-2.13 (m, 4H). MS(ES+): m/z=385.20 (38) [MH+], 302.14 (100) [MH+-piperidine]. HPLC: tR=1.78 min (polar—5 min, ZQ2).
Reaction SMILES: Cl.F[C:3](F)(F)[C:4]([OH:6])=[O:5].[CH2:9]([N:16]1[C:24]2[C:23](=[O:25])[N:22]([CH2:26][CH2:27][CH3:28])[C:21](=[O:29])[N:20]([CH2:30][CH2:31][CH3:32])[C:19]=2[N:18]=[C:17]1[CH:33]1[CH2:37]C[C:35](=C2SCCCS2)[CH2:34]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:44]O>ClCCl.[Hg](Cl)Cl>[CH2:9]([N:16]1[C:24]2[C:23](=[O:25])[N:22]([CH2:26][CH2:27][CH3:28])[C:21](=[O:29])[N:20]([CH2:30][CH2:31][CH3:32])[C:19]=2[N:18]=[C:17]1[CH:33]1[CH2:34][CH2:35][CH:3]([C:4]([O:6][CH3:44])=[O:5])[CH2:37]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCn1c(=O)c2c(nc(C3CCC(=C4SCCCS4)C3)n2Cc2ccccc2)n(CCC)c1=O
Reactant: CO
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: Cl[Hg]Cl
Solvent: ClCCl
Product: CCCn1c(=O)c2c(nc(C3CCC(C(=O)OC)C3)n2Cc2ccccc2)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.2 ml of 6N hydrochloric acid, 0.55 ml of trifluoroacetic acid and 2.38 g (8.8 mmol) of mercury(II)-chloride are successively added to a solution of 1.1 g (2.2 mol) of 7-benzyl-8-(3-(1,3-dithian-2-ylidene)-cyclopentyl)-1,3-dipropylpurine-2,6-dione in 30 ml of methanol and 6 ml of dichloromethane. The mixture is stirred for 4 hours at ambient temperature and then suction filtered over Celite. At -5° C., 90 mg of sodium borohydride are carefully added the filtrate, which is stirred for 30 minutes at 0° C., suction filtered over Celite and evaporated down. For purification the residue remaining is chromatographed on silica gel with a mixture of dichloromethane/methanol in the ratio 97:3. 0.72 g (72% of theory) of the title compound are obtained as a brownish oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6](O)=[O:7])#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:29][NH2:30]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([NH:29][NH2:30])=[O:7])#[N:2]
Reactant: NN
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(C(=O)NN)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (0.300 g, 1.46 mmol) in tetrahydrofuran (10.0 mL) was treated with 1,1′-carbonyldiimidazole (0.261 g, 1.61 mmol). After stirring 2 h at ambient temperature, hydrazine monohydrate (0.213 mL, 4.39 mmol) was added. After stirring an additional 2 h at ambient temperature, the reaction mixture was concentrated in vacuo. Purification via flash column chromatography (0-5% MeOH/EtOAc) gave the title compound as a white solid (0.304 g; 95%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.51 (br. s., 1H) 8.06 (d, J=2.3 Hz, 1H) 8.02 (dd, J=8.8, 2.3 Hz, 1H) 7.00 (d, J=8.8 Hz, 1H) 5.15 (br. s., 2H) 4.71 (qq, J=6.1 Hz, 1H) 1.40 (d, J=6.1 Hz, 6H). MS (ES+) m/e 220 [M+H]+.