Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:11]([O:12][CH3:13])=[CH:10][C:7]([CH2:8][OH:9])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)[CH:2]=[CH2:3].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:4]1[C:11]([O:12][CH3:13])=[CH:10][C:7]([CH2:8][O:9][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCc1cc([N+](=O)[O-])c(CO)cc1OC
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1cc([N+](=O)[O-])c(CO[Si](C)(C)C(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
229 mg of 4-allyl-5-methoxy-2-nitrobenzyl alcohol was dissolved in 5 ml of N,N-dimethylformamide. Thereafter, 0.17 g of imidazole and 0.23 g of t-butyldimethylsilyl chloride were added to the reaction solution while cooling on ice. The obtained mixture was stirred at room temperature for 2 hours. Thereafter, 34 mg of imidazole and 46 mg of t-butyldimethylsilyl chloride were further added to the reaction solution. The obtained mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and then washed with a saturated ammonium chloride aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 330 mg of the subject compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]2[S:34][C:33]([C:35]([OH:37])=O)=[N:32][C:31]=2[C:38]=1[N+:39]([O-:41])=[O:40].C(N(C(C)C)CC)(C)C.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1.CN(C1C=CC=CN=1)C>ClCCl.CCCCCCC.C(OCC)(=O)C>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]2[S:34][C:33]([C:35]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[O:37])=[N:32][C:31]=2[C:38]=1[N+:39]([O-:41])=[O:40]
Reactant: C1COCCN1
Reactant: COc1ccc2sc(C(=O)O)nc2c1[N+](=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2sc(C(=O)N3CCOCC3)nc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 33 %

Procedure:
980 mg (2.1 mmol; 1.1 eq.) of bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP) is added to 500 mg (1.97 mmol) of 5-methoxy-4-nitro-1,3-benzothiazole-2-carboxylic acid and 344 μl (1.97 mmol; 1 eq.) of diisopropylethylamine in solution in 40 ml of dichloromethane. The reaction mixture is maintained for 15 minutes under stirring at ambient temperature, then 202 μl (2.3 mmol; 1.2 eq.) of morpholine and a spatula tip's worth of dimethylaminopyridine are added to the medium which is maintained under stirring for 18 hours at ambient temperature. An insoluble part is then filtered and the solvent evaporated off under reduced pressure. The residue is then purified on a silica column (eluent: ethyl acetate/heptane: gradient of 30 to 70% over 40 minutes then for 5 minutes at 70% of ethyl acetate in heptane) and 210 mg (yield=33%) of expected product is obtained in the form of beige powder.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH3:17][O:18][CH2:19][CH2:20][OH:21]>>[CH3:17][O:18][CH2:19][CH2:20][O:21][C:8]1[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=[CH:15][N:16]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: COCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COCCOc1ncccc1C(=O)O
Temperature: 0 °C
Yield: 81 %

Procedure:
Potassium t-butoxide (45.0 g, 0.40 mol) was added portion-wise to ice-cold 2-methoxyethanol (175 ml), and the resulting solution added to a suspension of 2-chloronicotinic acid (30.0 g, 0.19 mol) in 2-methoxyethanol (175 ml). The reaction mixture was heated under reflux for 26 hours, then cooled and concentrated under reduced pressure. The residue was diluted with water (200 ml), the pH of the solution adjusted to 5 using concentrated hydrochloric acid, and extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried (MgSO4), evaporated under reduced pressure and azeotroped with toluene, to afford the title compound, (30.54 g, 81%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[K+].[K+].Br[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(OCC)(=O)C.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([C:15]2[CH:20]=[CH:19][C:18]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Reactant: Brc1ncccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(-c3ncccn3)cc2)CC1
Temperature: 100 °C
Yield: 79.9 %

Procedure:
4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (800 mg, 2.25 mmol), bis(pinacolate)diboron (856 mg, 3.37 mmol), PdCl2(dppf).CH2Cl2 (184 mg, 0.23 mmol), potassium acetate (660 mg, 6.74 mmol) were weighted into a sealed-tube. Methyl sulfoxide (20 ml) was added and the mixture was purged with nitrogen for 20 min before it was heated at 100° C. for 2 hr under nitrogen. The mixture was cooled to r.t. Potassium carbonate (1.55, 11.2 mmol), 2-bromopyrimidine (429 mg, 2.70 mmol) and water (10 ml) were added. The mixture was again purged with nitrogen for 20 min. Palladium tetrakistriphenylphosphine (260 mg, 0.23 mmol) was added and the final mixture was stirred at 100° C. for a further 2 hr. After being cooled to r.t., ethyl acetate and water were added. The mixture was filtered through a pad of Celite. Layers were separated and the organic layer was washed with water (×2). The combined aqueous layers were extracted with ethyl acetate (×1). The combined organic layers were dried (MgSO4) and filtered. Solvents were removed in vacuum and column chromatography [ethyl acetate-hexane, 1:1 (v/v)] gave 4-hydroxy-4-(4-pyrimidin-2-ylphenyl)-piperidine-1-carboxylic acid tert-butyl ester (639 mg, 80%) as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cc(C(=O)CC(=O)OC(C)(C)C)ccn2)on1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(-c2cc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)C)cc3NC(=O)OC(C)(C)C)ccn2)on1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and 3-[2-(3-methyl-isoxazol-5-yl)-pyridin-4-yl]-3-oxo-propionic acid tert.-butyl ester (Example K6) (170 mg, 0.56 mmol) according to the general procedure M. Obtained as a brown solid (206 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:43])=[C:37]([S:39](Cl)(=[O:41])=[O:40])[CH:38]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:37]4[CH:38]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=4[CH3:43])(=[O:40])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cc(F)ccc4C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 5-fluoro-2-methyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=593.7)=92%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[S:10][C:3]=12.[CH3:16][NH:17][C:18]([C:20]1[C:28]2[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=2)[N:22]([CH3:30])[C:21]=1[CH3:31])=[O:19].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:30][N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[C:25]([O:29][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[S:10][C:3]=34)[CH:24]=2)[C:20]([C:18]([NH:17][CH3:16])=[O:19])=[C:21]1[CH3:31]
Reactant: CN(C)C(=O)c1cc2nccc(Cl)c2s1
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N(C)C)sc34)ccc12
Yield: 72.5 %

Procedure:
This material was prepared by the reaction 7-chloro-N,N-dimethylthieno[3,2-b]pyridine-2-carboxamide 33a (0.077 g, 0.32 mmole) and 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.070 g, 0.32 mmole) and Cs2CO3 (0.104 g, 0.32 mmole) in a manner as previously described for example 1 to give a pale yellow solid (0.098 g, 73%). 1H NMR (300 MHz, CD3OD) δ8.38 (1H, d, J=5.5 Hz), 7.75 (1H, d, J=8.7 Hz), 7.66 (1H, s), 7.28 (1H, d, J=2.1 Hz), 6.94 (1H, dd, J=2.1, 8.7 Hz), 6.60 (1H, d, J=5.5 Hz), 3.61 (3H, s), 3.21 (6H, m), 2.87 (3H, s), 2.56 (3H, s). ESIMS (MH+): 423.05.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[N:16]=[C:15]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:36]=[CH:37][CH:38]=2)[O:22][CH2:23][C:24]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:25]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].C(C#N)(C)=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:24]([CH2:23][O:22][C:21]2[CH:36]=[CH:37][CH:38]=[C:19]([O:18][CH2:17][C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:16]=3)[CH:20]=2)[C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1c(C)cccc1COc1cccc(OCc2cccc(Cl)n2)c1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Solvent: O
Product: CCOC(=O)c1c(C)cccc1COc1cccc(OCc2cccc(-c3ccccc3)n2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A solution of phenylboronic acid (74.0 mg, 0.607 mmoles), ethyl 2-[3-(6-chloropyridin-2-ylmethoxy)-phenoxymethyl]-6-methylbenzoate (250 mg, 0.607 mmoles, example 6v), and sodium carbonate (77.8 mg, 1.21 mmoles) in 1:1H2O:AcCN (8 mL) is stirred under vacuum for five minutes. The reaction is placed under nitrogen, and tetrakis(triphenylphosphine)-palladium(0) (60.7 mg) is added followed by heating to 90° C. After two hours, another portion (15 mg) of phenylboronic acid is added. After another hour heating is stopped. Distilled water (10 mL) is added, followed by extraction with methylene chloride (twice with 20 mL). The organic extracts are combined and concentrated, and the resulting residue is purified by column chromatography (silica, 6:1 hex:EtOAc) to yield the title compound. MS (ESI) 454 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][N:20]1[C:25](=[O:26])[C:24]2=[CH:27][NH:28][N:29]=[C:23]2[N:22]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:21]1=[O:34].O>CC(C)=O>[CH3:19][N:20]1[C:25](=[O:26])[C:24]2=[CH:27][N:28]([CH2:2][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=[CH:5][CH:4]=3)[N:29]=[C:23]2[N:22]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:21]1=[O:34]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c[nH]nc21
Reactant: ClCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3cccc4ccccc34)nc21
Temperature: 25 °C
Yield: 89.3 %

Procedure:
In accordance with the teaching of German Patent No. 63,381, 1-(chloromethyl)-naphthalene (2.2 g), potassium carbonate (1.6 g) and 5-methyl-7-(2-methylpropyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (2.5 g) were combined in acetone (40 ml) and heated under reflux for 3 hours and then cooled to ambient temperature. Water (200 ml) was added and the precipitated solid was collected by filtration. The solid was triturated with isohexane and then dried in vacuo to give the title compound (3.64 g).
Reaction SMILES: C1C=C(Cl)C=C([C:8](OO)=[O:9])C=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[C:24]3[CH2:34][CH2:33][N:32]([C:35]4[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][N:36]=4)[CH2:31][C:25]=3[N:26]=[C:27](SC)[N:28]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C[O-].[Na+]>C(O)C>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[C:24]3[CH2:34][CH2:33][N:32]([C:35]4[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][N:36]=4)[CH2:31][C:25]=3[N:26]=[C:27]([O:9][CH3:8])[N:28]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(c1ncccc1Cl)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(c1ncccc1Cl)C2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
m-CPBA (148 mg, 0.6 mmol) was added to a solution of N-(4-tert-butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine from Example 28.C. (88 mg, 0.2 mmol) in ethanol (7 mL) and stirred at room temperature for 1 hr. Solid thus formed was filtered out and dried in vacuo (50 mg). The solid was suspended in methanol (5 mL) and sodium methoxide (9 mg, 0.165 mmol) was added and stirred at 60° C. overnight. Solvent was removed in vacuo and residue was dissolved in ethyl acetate, washed with water, sodium hydrosulfite aqueous solution, brine and dried over sodium sulfate. Purified by flash chromatography to yield the product as a white solid (33 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.[CH2:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:14]>C(O)C>[CH2:9]([O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:15]([CH2:13][CH3:14])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1)[C:10]#[C:11][CH3:12]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: CCNCc1ccccc1
Solvent: CCO
Product: CC#CCOc1cc(N(CC)Cc2ccccc2)ncn1
Temperature: 25 °C
Yield: 54.5 %

Procedure:
To 4 ml of ethanol were added 0.5 g of 4-chloro-6-(2-butynyloxy)pyrimidine and 0.68 g of N-ethyl-N-benzylamine, followed by heating under reflux for 6 hours. The reaction mixture was then left for cooling to room temperature and concentrated under reduced pressure. A saturated aqueous ammonium chloride solution was poured onto the residue, which was extracted three times with ethyl acetate. The organic layers were combined and washed with a saturated aqueous sodium chloride solution, and the combined organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.42 g of 6-(2-butynyloxy)-4-(N-ethyl-N-benzylamino)pyrimidine (the present compound (129)).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH:11]=O.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]1=[S:23].[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>CO.[Pd]>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]1=[S:23]
Reactant: O=CC1CCc2ccccc2O1
Reactant: NCCCN1CCCNC1=S
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CO
Product: S=C1NCCCN1CCCNCC1CCc2ccccc2O1
Reaction time: 48 h
Yield: 7 %

Procedure:
A mixture of 3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (0.015 mol) and 1-(3-aminopropyl)tetrahydro-2(1H)-pyrimidinethione (0.01 mol) in methanol (150 ml) was hydrogenated for 2 days at room temperature (atmospheric pressure) with palladium on activated carbon (2 g) as a catalyst. After uptake of H2 (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 95/5). The pure fractions were collected and the solvent was evaporated. The residue (0.3 g) was dissolved in ethanol (30 ml) and converted into the ethanedioic acid salt (1:1) with ethanedioic acid (0.3 g; 0.0124 mol). The precipitate was filtered off and dried (vacuum), yielding 0.3 g (7%) of (±)-1-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]tetrahydro-2(1H)-pyrimidinethione ethanedioate (1:1); mp. 217.6° C. (comp. 14).
Reaction SMILES: O.C1(C)C=CC(C([C@](C(O)=O)(O)[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=[O:9])=CC=1.[CH2:30]([N:33]1[C:37]([CH2:38][S:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[CH:36][N:35]=[CH:34]1)[CH2:31][CH3:32].Cl>C(OCC)(=O)C>[CH2:30]([N:33]1[C:37]([CH2:38][S:39]([C:40]2[CH:41]=[CH:42][C:43]([NH2:46])=[CH:44][CH:45]=2)=[O:9])=[CH:36][N:35]=[CH:34]1)[CH2:31][CH3:32]
Reactant: CCCn1cncc1CSc1ccc(N)cc1
Reactant: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCCn1cncc1CS(=O)c1ccc(N)cc1

Procedure:
To (−)-4-{[(1-propyl-1H-imidazol-5-yl)methyl]sulfenyl}phenylamine di-p-toluoyl-D-tartarate monohydrate (5 g) were added 1N hydrochloric acid (25 ml) and ethyl acetate (15 ml) to effect reverse extraction. To the aqueous layer was added aqueous 25% potassium carbonate solution (25 ml) (pH 9) and the mixture was extracted with 25 ml of ethyl acetate-IPA (4:1) three times. The organic layer was washed with saturated brine (25 ml) and dried with magnesium sulfate. The solvent was distilled off to give (−)-4-{[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenylamine.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1.B([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33])(O)O.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O.CCOCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[CH3:33][O:32][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:23]=1[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1)[C:27]([OH:29])=[O:28]
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1cc(C(=O)O)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)O)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 120 °C

Procedure:
To a microwave vial was added 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 1-1, 100 mg, 0.35 mmol), 4-borono-3-methoxybenzoic acid (76 mg, 0.39 mmol), PdCl2(dppf).CH2Cl2 (29 mg, 0.035 mmol), Na2CO3 (112 mg, 1.06 mmol), DMF (2 mL) and water (0.5 mL). The microwave vial was sealed and heated in a microwave at 120° C. for 45 min. The crude reaction mixture was cooled and diluted in water and ether. The aqueous layer was extracted with ether. The resultant emulsion was diluted in water and 1 M NaOH. The aqueous layer was acidified with 1 M HCl slowly and extracted again with ether. The organic layer was concentrated under reduced pressure, and the resulting precipitate was suspended in 10 mL MeOH and filtered. The filtrate was concentrated and used without further purification. LCMS Rt=0.63 min (condition B); MS (M+1)=399.0
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][OH:31])=[CH:25][CH:24]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CCO.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][OH:31])=[CH:25][CH:24]=1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Reactant: CC1(C)OB(c2ccc(CCO)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)c1n[nH]c2cc(Cl)c(-c3ccc(CCO)cc3)cc12
Temperature: 130 °C
Yield: 13.4 %

Procedure:
To a solution of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (75 mg, 0.27 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol (75 mg, 0.30 mmol) in EtOH (0.5 mL) and toluene (0.5 mL) was added 2 N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol). The reaction mixture was degassed with N2 for 5 minutes, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11.4 mg, 0.014 mmol) and degassed with N2 for another 5 minutes. The suspension was sealed in a pressure tube and heated to 130° C. for 1 hour. As the reaction progressed, the suspension became clear, turned to orange and then dark brown. The reaction mixture was diluted with EtOAc (5 mL) and water (5 mL), and filtered through a syringe filter. The aqueous layer was acidified to pH 5 by 1 N HCl solution, and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% Formic acid in water (v/v); Mobile phase B: 0.05% Formic acid in MeCN (v/v); HOLD at 80.0% H2O/20.0% MeCN for 1.0 min. 80.0% H2O/20.0% MeCN linear to 60.0% H2O/40.0% MeCN in 6.75 min, linear to 0% H2O/100% MeCN to 7.0 min. HOLD at 0% H2O/100% MeCN from 7.0 to 8.0 min. Flow: 30 mL/min) to provide the title compound (11.5 mg, 13% yield). MS (ES+) 317.1 (M+H)+. Retention time=2.27 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](/[N:19]=[N:20]/[C:21]2[CH:26]=[CH:25][C:24]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][OH:30])=[CH:23][CH:22]=2)[S:5][C:6]=1[CH:7]=[C:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].Cl[S:34]([OH:37])(=[O:36])=[O:35]>C1COCC1>[S:34]([OH:37])([O:30][CH2:29][CH2:28][N:27]([C:24]1[CH:23]=[CH:22][C:21](/[N:20]=[N:19]/[C:4]2[S:5][C:6]([CH:7]=[C:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])=[C:2]([Cl:1])[N:3]=2)=[CH:26][CH:25]=1)[CH2:31][CH3:32])(=[O:36])=[O:35]
Reactant: CCN(CCO)c1ccc(/N=N/c2nc(Cl)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: C1CCOC1
Product: CCN(CCOS(=O)(=O)O)c1ccc(/N=N/c2nc(Cl)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Temperature: 0 °C

Procedure:
0.5 g (1.07 mmol) 2-{[4-chloro-2-((E)-{4-[ethyl(2-hydroxyethyl)amino]-phenyl}-diazenyl)-1,3-thiazol-5-yl]methylidene}-1H-indene-1,3(2H)-dione were dissolved in 50 ml THF and cooled to 0° C. Then 0.19 g (1.60 mmol) chlorosulfonic acid were added slowly drop by drop with stirring. After the addition was completed, the reaction mixture was heated under reflux for 4 hours, allowed to cool to room temperature and stirred overnight. After further cooling in an ice bath the formed precipitate was filtered off, washed with a little cold THF and dried at 40° C. in vacuum.