Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:19][CH2:18]4)[C:11]=3[C:10](=[O:20])[NH:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[CH:23]=[C:24]([CH3:32])[C:25]2[N:26]([C:28]([CH3:31])=[N:29][N:30]=2)[N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:19][CH2:18]4)[C:11]=3[C:10](=[O:20])[N:9]2[C:22]2[CH:23]=[C:24]([CH3:32])[C:25]3[N:26]([C:28]([CH3:31])=[N:29][N:30]=3)[N:27]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)nn2c(C)nnc12
Reactant: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)NC2=O
Product: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3n1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 110 using 4-(4-chlorophenyl)-1-cyclopropyl-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 85.6) and 6-chloro-3,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine (Step 111.2). The crude material was first purified by silica gel column chromatography (EtOAc/MeOH 0.5-1%), followed by preparative achiral SFC (column 4-Ethyl-pyridine, gradient 9-14% in 6 min_total 11 min). tR; 4.66 min (HPLC 1); tR: 1.08 min (LC-MS 2); ESI-MS: 434 [M+H]+ (LC-MS 2); Rf=0.14 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.08 (m, 2H) 1.21-1.26 (m, 2H) 1.90 (s, 3H) 2.51 (s, 3H) 2.57 (d, J=1.2 Hz, 3H) 3.82 (dt, J=7.4, 3.7 Hz, 1H) 6.45 (s, 1H) 7.32-7.37 (m, 2H) 7.42-7.47 (m, 2H) 8.08-8.14 (m, 1H).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH2:10]COC)[N:7]2[NH:14][C:15](=[O:17])[N:16]=[C:6]2[C:5]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[CH:21][CH:20]=1)[CH2:2][CH3:3].CC=C(C)C.B(Br)(Br)[Br:42]>C(Cl)(Cl)Cl>[CH2:1]([C:4]1[N:9]=[C:8]([CH2:10][Br:42])[N:7]2[NH:14][C:15](=[O:17])[N:16]=[C:6]2[C:5]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[CH:21][CH:20]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(CCOC)n2[nH]c(=O)nc2c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: BrB(Br)Br
Agent: CC=C(C)C
Solvent: ClC(Cl)Cl
Product: CCCc1nc(CBr)n2[nH]c(=O)nc2c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g of 7-n-propyl-5-methoxyethyl-8-{[2 '- (5-tetrazolyl)-4-biphenylyl]methyl}-1,2,4-triazolo[1,5-c]pyrimidin-2 (3H) -one, prepared in Example 169, are dissolved in 50 ml of chloroform stabilised with amylene. 0.7 ml of boron tribromide is added and the mixture is stirred for 8 hours at room temperature; the derivative 7-n-propyl-5-bromomethyl-8-{[2 '- (5-tetrazolyl ) -4-biphenylyl]methyl}-1,2,4-triazolo[1,5-c]pyrimidin-2(3H )-one thereby formed is taken up with dilute sodium hydroxide solution and stirred again for 6 hours. The aqueous phase is then separated after settling has taken place and acidified by bubbling in sulphur dioxide, and the crystals formed are drained, washed with acetone and then dried to give 0.6 g of 7-n-Propyl-5-hydroxymethyl-8-{[2'-(5 -tetrazolyl ) - 4 -biphenylyl ]methyl }- 1,2,4 -triazolo [ 1,5-c]pyrimidin-2(3H)-one in the form of crystals of melting point 182°-183° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][N:8]=[C:7](C=O)[CH:6]=1)[CH3:2].[CH:14]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])OCC.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:6]=[CH:7][N:8]=[C:9]([CH:14]([O:18][CH2:19][CH3:20])[O:21][CH2:22][CH3:23])[CH:10]=1)[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)c1ccnc(C=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccnc(C(OCC)OCC)c1
Temperature: 110 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-formyl-isonicotinic acid ethyl ester (5.0 g, 0.027 mol) in ethanol (9 mL) was added triethyl orthoformate (6.2 mL, 0.037 mol) followed by a solution of 6N hydrochloric acid in ethanol (1.5 mL). The mixture was heated to 110° C. (reflux) for 1.5 h, cooled to rt and solid potassium carbonate (1.80 g) added. The mixture was stirred for 5 min, concentrated in vacuo, and redissolved in diethyl ether (100 mL). The reaction was filtered through silica and the resulting cake washed with diethyl ether (50 mL). The filtrated was concentrated in vacuo to give 2-diethoxymethyl-isonicotinic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=3)[N:12]=[C:11]([C:23](OCC)=[O:24])[CH:10]=2)=[CH:5][CH:4]=1.[NH3:30]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=3)[N:12]=[C:11]([C:23]([NH2:30])=[O:24])[CH:10]=2)=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1cc(OCc2ccc(OC)cc2)c2cc(C(F)(F)F)ccc2n1
Reactant: N
Product: COc1ccc(COc2cc(C(N)=O)nc3ccc(C(F)(F)F)cc23)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A methanolic solution of ethyl 4-((4-methoxybenzyl)oxy)-6-(trifluoromethyl)quinoline-2-carboxylate (53 g, 131 mmol) from above step A, was cooled in an ice bath and saturated with ammonia by bubbling in ammonia. The flask was capped and stirred at room temp for 20 h. The white precipitate that formed was collected by filtration and washed with a small amount of MeOH and dried under vacuum to give the title compound.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:4]1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][C:24]=1[C:31]([F:34])([F:33])[F:32]>>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:19]2[CH2:18][CH2:17][C:5]3([O:4][C:3](=[O:2])[N:7]([C:8]4[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:15][CH:16]=4)[CH2:6]3)[CH2:21][CH2:20]2)=[CH:25][C:24]=1[C:31]([F:32])([F:33])[F:34]
Reactant: O=C(O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Reactant: O=Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Product: O=C(O)c1ccc(N2CC3(CCN(Cc4ccc(Cl)c(C(F)(F)F)c4)CC3)OC2=O)cc1

Procedure:
The title compound was prepared from 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoic acid hydrochloride salt (20 mg, 0.064 mmol; Example 5-1, Step 4) and 4-chloro-3-trifluoromethylbenzaldehyde (14.68 mg, 0.071 mmol), following essentially the same procedure described in Example 7-1. The title compound was obtained as a white solid (17.4 mg).
Reaction SMILES: ClC(Cl)C(O)=O.N[C:8]1[N:9]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([CH:39]3[CH2:41][CH2:40]3)=[CH:31][CH:30]=2)[C:10]([S:13][CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][C:19]=2[Cl:28])=[O:16])=[N:11][N:12]=1.N([O-])=O.[Na+].[Br:46]CBr>>[Br:46][C:8]1[N:9]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([CH:39]3[CH2:41][CH2:40]3)=[CH:31][CH:30]=2)[C:10]([S:13][CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][C:19]=2[Cl:28])=[O:16])=[N:11][N:12]=1
Reactant: BrCBr
Reactant: Nc1nnc(SCC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)n1-c1ccc(C2CC2)c2ccccc12
Agent: O=C(O)C(Cl)Cl
Agent: O=N[O-]
Agent: [Na+]
Product: NS(=O)(=O)c1ccc(NC(=O)CSc2nnc(Br)n2-c2ccc(C3CC3)c3ccccc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
Dichloroacetic acid (180 uL, 2.2 mmol) was added to a suspension of 2-[5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-chloro-4-sulfamoylphenyl)acetamide (0.59 g, 1.1 mmol), sodium nitrite (1.5 g, 22 mmol) and BTEABr (0.91 g, 3.3 mmol) in dibromomethane (30 mL). The reaction mixture was stirred at room temperature for 4 hours, then extracted with dichloromethane and sodium bicarbonate in water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield 2-[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-chloro-4-sulfamoylphenyl)acetamide (224 mg, 31%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:14]([NH:17][CH3:18])(=[O:16])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1>CC(O)C>[CH3:18][NH:17][S:14]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([F:11])([F:13])[F:12])=[C:2]([NH:1][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:3]=1)(=[O:15])=[O:16]
Reactant: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(N)c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Solvent: CC(C)O
Product: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(Nc2ncnc3cc(OCc4ccccc4)c(OC)cc23)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
A solution of 3-amino-N-methyl-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonamide (3.0 g, 10.7 mmol) in i-PrOH (100 mL) was treated with 4-chloro-6-(methyloxy)-7-[(phenylmethyl)oxy]quinazoline (3.2 g, 10.7 mmol, prepared according to J. Med. Chem. (1999) 42 5369) and stirred at 80° C. for 2 hours before being concentrated. The residue was washed with petroleum ether and dried to give N-methyl-3-({6-(methyloxy)-7-[(phenylmethyl)oxy]-4-quinazolinyl}amino)-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonamide (4.2 g, 72%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.42 (br. s., 1 H), 8.75 (s, 1 H), 8.20 (s, 1 H), 7.80-7.84 (m, 2 H), 7.49-7.57 (m, 4 H), 7.35-7.49 (m, 4 H), 5.34 (s, 2 H), 4.91 (q, J=8.82 Hz, 2 H), 3.99 (s, 3 H), 2.45 (d, J=5.07 Hz, 3 H). MS (m/z) 549.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>C(N(CC)CC)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[C:22](=[O:23])[NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([F:13])([F:25])[F:24]
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: O=c1cc(O)c2ccccc2o1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1C(F)(F)F)c1c(O)c2ccccc2oc1=O

Procedure:
According to the procedure of example 17, 4-hydroxycoumarin (2.00 g. 12.8 mmol) and 2-trifluoromethylphenylisocyanate(1.93 ml, 12.8 mmol) were reacted in the presence of triethylamine (0.05 ml) to generate the title compound as an off-white solid, mp 157-159° C., (2.2 g, 6.30 mmol, 49.3%). Analysis: Calculated for C17H10NO4F3 : C, 58.45; H, 2.86; N, 4.01. Found: C, 58.47; H, 3.04; N, 4.02. 1H NMR (CDCl3): 8.06 (d, J=7.8 Hz, 2H), 7.70 (d, J=8.8 Hz, 2H), 7.62 (t, J=7.8 Hz, 1H), 7.38 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH2:19])[CH2:11][C@@H:10]2[CH3:20])=[O:8])=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.N1C=CC=CC=1.C(OCC)(=O)C>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:23][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH:19][C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=3)[CH2:11][C@@H:10]2[CH3:20])=[O:8])=[CH:21][CH:22]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: C[C@H]1C[C@@H](N)c2ccccc2N1C(=O)c1ccc(N(C)C)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H](Nc2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc(N(C)C)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
To a solution of (±)-cis-1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-4-aminoquinoline (423 mg, 1.36 mmol) in DMF (15 mL, dry) was added 4-chlorophenylboronic acid (425 mg, 2.72 mmol), pyridine (322 mg, 330 uL, 4.08 mmol) and copper(II)acetate (494 mg, 2.72 mmol). The heterogeneous green mixture was stirred open to air for 1 h and then warmed to 60° C. and stirred over night (14 h). The mixture was then cooled to rt, poured into rapidly stirred ethyl acetate (150 mL); solids were removed by filtration. The extracts were washed several times with water and then once with brine. The extracts were then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (100% hexanes to 50/50 hexanes/ethyl acetate gradient) to afford the aniline product (120 mg, 22%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:13][C:14](=[O:16])[CH3:15].[I-].[K+]>CC(C)=O>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=1)([O:8][CH3:9])=[O:7]
Reactant: CC(=O)CCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCC(C)=O)cc1
Yield: 188.2 %

Procedure:
A mixture of methyl 4-hydroxybenzoate (30.4 g), chloroacetone (8.5 g) potassium carbonate (54 g) and potassium iodide (33.3 g) was refluxed in acetone for 4 hours. The reaction mixture was cooled, the solids filtered and the solvent evaporated. The residue was partitioned between water and ether, the layers separated and the organic layer dried (MgSO4). Removal of the solvent gave the title compound (36 g). τ (CDCl3) 7.75 (3H, s), 6.11 (3H, s), 5.39 (2H, s), 3.09 (2H, d, J=9 Hz), 2.0 (2H, d, J=9 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH2:35][CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>O1CCOCC1>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:33]=[CH:32][O:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Reactant: NC1CCOCC1
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(NC3CCOCC3)n2)c1F)c1ccoc1

Procedure:
Following a procedure analogous to the procedure described in example 300 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (110 mg, 0.211 mmol), 4-aminotetrahydropyrane (107 mg, 1.056 mmol) in 1,4-dioxane (2 mL), the title compound was obtained as a brown foam (20 mg, 0.032 mmol, 15%). 1H NMR (400 MHz, DMSO-d6) ppm 1.33-1.63 (m, 2H), 1.75 (qd, J=11.96, 4.29 Hz, 4H), 1.99-2.05 (m, 2H), 3.19-3.39 (m, 5H), 3.47 (td, J=11.62, 1.77 Hz, 2H), 3.78-3.90 (m, 2H), 3.90-3.98 (m, 2H), 6.66 (d, J=1.26 Hz, 1H), 7.23-7.38 (m, 3H), 7.45 (t, J=6.95 Hz, 1H), 7.82 (t, J=1.77 Hz, 1H), 8.11 (d, J=4.55 Hz, 1H), 8.28 (s, 1H), 10.32 (s, 1H); MS (ESI): 586.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11].[I:20]N1C(=O)CCC1=O>C(#N)C.C(O)(=O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[C:17]([I:20])[CH:18]=1)[CH3:11]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(Oc1cccnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(Oc1cc(I)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
To a solution of 3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine (10.0 g, 33.2 mmol) in acetonitrile (600 mL) and acetic acid (120 mL) was added N-iodosuccinimide (11.2 g, 49.8 mmol). The mixture was stirred at room temperature for 4 hr and the reaction was quenched with Na2S2O5 solution. After evaporation, the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2N NaOH solution, brine, and dried over Na2SO4. The crude product was purified on a silica gel column to provide 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine (7.1 g, 50% yield). MS m/z 427 [M+1]
Reaction SMILES: C([NH:4][CH:5]([C:12]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:14]=2[N:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.Cl>C(O)C>[Cl:21][C:19]1[CH:18]=[CH:17][C:15]2[NH:16][C:12]([CH:5]([NH2:4])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:13][C:14]=2[CH:20]=1
Reactant: CC(=O)NC(c1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CCO
Product: NC(c1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 50 °C

Procedure:
1.34 g (4.47 mmol) N-acetyl-1-(5-chloro-1H-benzimidazol-2-yl)-1-phenylmethylamine in 9 ml of ethanol are combined with 18 ml of conc. hydrochloric acid and heated to 50° C. for 2 days. The reaction mixture is evaporated down i. vac. and twice taken up in ethanol and evaporated down again.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:11]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCBr
Reactant: OCCCCCCCO
Product: CCCCCCCCCCOCCCCCCCO

Procedure:
3-(7-Decyloxyheptylthio)-propanol (m.p. 28°-32° C.), obtained by reacting heptane-1,7-diol with 1-bromodecane to give 7-decyloxyheptanol, bromination thereof to give 7-decyloxyheptyl bromide, reaction with methyl β-mercaptopropionate to give methyl β-(7-decyloxyheptylthio)-propionate and reduction with lithium aluminium hydride, is reacted in the manner described in Example 20C to give the desired choline ester in a yield of 17% of theory. The water-soluble, white crystals sinter at 53° C. and melt at 224° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[N:12]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])#[N:2].Cl.[NH2:27][OH:28].C(N(CC)CC)C>CCO>[CH3:25][N:23]([CH3:24])[C:21](=[O:22])[CH2:20][N:12]([C@@H:7]1[C:8]2[C:4](=[C:3]([C:1](=[NH:2])[NH:27][OH:28])[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CN(C)C(=O)CN(C(=O)OC(C)(C)C)[C@H]1CCc2c(C#N)cccc21
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)C(=O)CN(C(=O)OC(C)(C)C)[C@H]1CCc2c(C(=N)NO)cccc21
Temperature: 85 °C
Yield: 98.4 %

Procedure:
Prepared using General Procedure 3. To a solution of (S)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-yl(2-(dimethylamino)-2-oxoethyl)carbamate (3.8 g, 11.07 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (1.92 g, 27.67 mmol) and triethylamine (2.8 g, 27.67 mmol). The reaction solution was heated to 85° C. for 2 h. The solvent was removed under vacuum and the residue partitioned between DCM (3×10 mL) and water (10 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum to produce 4.10 g (87.7%) of (S)-tert-butyl 2-(dimethylamino)-2-oxoethyl(4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)carbamate, which was 65% pure and used directly in the next experiment. LCMS-ESI (m/z) calculated for C19H28N4O4; 376.45. found 377.2 [M+H]+, tR=1.85 min.
Reaction SMILES: C1[N:5]([C@@H:6]2[O:10][C@@H:9]3COP(O)(O[C@H]3[C@H:7]2O)=O)[C:4]2NC(N)=N[C:21](=O)[C:3]=2N=1.[C:24]([S:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([OH:38])[CH:36]=2)[N:31]([CH2:39][C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[C:30]=1[CH2:55][C:56]([CH3:63])([CH3:62])[C:57]([O:59][CH2:60][CH3:61])=[O:58])([CH3:27])([CH3:26])[CH3:25]>>[CH2:60]([O:59][C:57](=[O:58])[C:56]([CH3:62])([CH3:63])[CH2:55][C:30]1[N:31]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([C:3]3[CH:21]=[CH:7][C:6]([O:10][CH3:9])=[N:5][CH:4]=3)=[CH:44][CH:45]=2)[C:32]2[C:37]([C:29]=1[S:28][C:24]([CH3:26])([CH3:27])[CH3:25])=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH3:61]
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Nc1nc(=O)c2ncn([C@@H]3O[C@@H]4COP(=O)(O)O[C@H]4[C@H]3O)c2[nH]1
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(-c2ccc(OC)nc2)cc1
Yield: 86 %

Procedure:
The cGMP starting material used for the process was ethyl 3-(3-(tert-butylthio)-5-hydroxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-indol-2-yl)-2,2-dimethylpropionate from Example 3. Ethyl 3-(3-(tert-butylthio)-5-hydroxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-indol-2-yl)-2,2-dimethylpropionate from Example 3, was scaled up to 2.0 kg. In order to ensure optimal Suzuki coupling conditions, the amount of time needed to deoxygenate the mixture was increased from about 5-10 minutes to about 30-45 minutes. Workup and isolation of the product proceeded as described above to yield 1.49 kg of 3-[5-hydroxy-3-(2-methyl-2-propylthio)-1-[4-(2-methoxypyrid-5-yl)benzyl]indol-2-yl]-2,2-dimethylpropionic acid ethyl ester in about 86% yield.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CC1(C)C(C)(C)OB([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.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]>[CH:4]([C:3]1[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:2]=1[C:22]1[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=1)=[O:5]
Reactant: O=Cc1ccc(C(F)(F)F)cc1Br
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2C=O)cn1
Temperature: 25 °C

Procedure:
2-bromo-4-(trifluoromethyl)benzaldehyde (1.3 g, 5.1 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate, prepared as in example 19, (2.7 g, 7.7 mmol), Pd(dppf)Cl2 (421 mg, 0.5 mmol), and K2CO3 (1.4 g, 10.3 mmol) were dissolved in 1,4-dioxane (40 mL) and water (10 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=S.[NH3:34]>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=[NH:34]
Reactant: N
Reactant: COc1cc2c(NC(=S)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2c(NC(=N)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1

Procedure:
Mercuric(II) oxide (0.059 g) was added to a mixture of 1-(2,6-dimethylphenyl)-3-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]thiourea (0.105 g), a 2M solution of ammonia in methanol (3 ml) and chloroform (1 ml) and the reaction mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a 2M solution of ammonia in methanol as eluent. There was thus obtained the title compound (0.074 g); NMR Spectrum: (CDCl3) 1.39-1.53 (m, 2H), 1.87-2.02 (q, 5H), 2.29 (s, 3H), 2.36 (s, 6H), 2.9 (d, 2H), 4.01 (m, 5H), 5.79 (br s, 1H), 7.16 (s, 1H), 7.19 (m, 3H), 7.87 (s, 1H), 8.57 (s, 1H); Mass Spectrum: M+H+ 449.