Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[CH:13][CH:12]=3)[C:3]=12.[CH:36]1([CH:39]=O)[CH2:38][CH2:37]1.N1CCCCC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:39][CH:36]4[CH2:38][CH2:37]4)[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[CH:13][CH:12]=3)[C:3]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Solvent: C1CCNCC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
Into a 10 mL round-bottom flask, was placed a solution of 3-[(3R)-3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (60 mg, 0.13 mmol, 1.00 equiv) in methanol (10 mL), cyclopropane-carbaldehyde (50 mg, 0.71 mmol, 5.61 equiv), and piperidine (70 mg, 0.82 mmol, 6.46 equiv). The resulting solution was stirred for 30 min at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 0.015 g (23%) of the title compound as an off-white solid. LC-MS0: (ES, m/z): 524 [M+H]+. H-NMR (CD3OD, ppm) 8.270 (1H, s), 7.711 (2H, d), 7.316˜7.242 (4H, m), 7.149 (2H, d), 6.450 (1H, d), 4.872 (1H, s), 4.192 (1H, s), 3.966 (2H, d), 3.556˜3.488 (1H, m), 2.392˜2.363 (1H, m), 2.253˜2.209 (2H, m), 1.951 (1H, s); 1.306-1.181 (3H, m); 0.918-0.793 (2H, m)
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH2:21][CH3:22])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:37][CH2:36][C:35]2[CH:38]=[CH:39][C:40]([NH2:42])=[CH:41][C:34]=2[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:37][CH2:36][C:35]2[CH:38]=[CH:39][C:40]([NH:42][C:2]3[N:23]=[C:5]4[C:6]([C:10]5[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=5[O:20][CH2:21][CH3:22])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:41][C:34]=2[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Reactant: CCOc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Product: CCOc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nc12

Procedure:
2-Chloro-8-(2-ethoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.500 g, 2.15 mmol) and 2-ethoxy-5-trifluoromethylbenzeneboronic acid (0.755 g, 3.23 mmol) in a manner analogous to Example 311a to give product (0.645 g, 88%). MS=342 (MH)+. 318b) 7-[8-(2-Ethoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-ethoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.640 g, 1.87 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.590 g, 2.25 mmol) in a manner analogous to Example 311b to give product (1.06 g, 99%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.55 (s, 1H), 8.78 (d, 1H), 7.98 (s, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.42 (m, 2H), 7.35 (d, 1H), 7.08 (t, 1H), 7.00 (d, 1H), 4.15 (q, 2H), 3.42 (m, 4H), 2.78 (m, 4H), 1.41 (s, 9H), 1.22 (t, 3H): MS=568 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Reactant: N#Cc1ccc(Br)cc1
Product: Cc1cc(N2CCCC2)c2ccc(Oc3ccc(C#N)cc3)cc2n1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 4-bromobenzonitrile, whereby the product was isolated as free base, 4-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-benzonitrile as a white solid. ISP mass spectrum, m/e 330.5 (M+1 calculated for C21H19N3O: 330).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][NH:24][C:25]([C:27]1[S:28][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:31]=1)=[O:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][NH:24][C:25]([C:27]1[S:28][C:29]([C:32]([NH:34][N:35]=[C:15]([C:12]2[C:13]([OH:14])=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[S:10][CH:11]=2)[CH3:17])=[O:33])=[CH:30][CH:31]=1)=[O:26]
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: NNC(=O)c1ccc(C(=O)NCC2CCCO2)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CC(=NNC(=O)c1ccc(C(=O)NCC2CCCO2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 64.4 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (22 mg, 0.075 mmol) in isopropanol (2.0 mL) was heated with 5-(hydrazinocarbonyl)thiophene-2-carboxylic acid (tetrahydrofuran-2-ylmethyl)amide (20 mg, 0.075 mmol) prepared in Reference Synthetic Example 2 and 3 mg of p-toluenesulfonic acid monohydrate at 105° C. for 17 hours and allowed to cool to room temperature. The precipitated solid was collected by filtration, washed with 1 mL of isopropanol and 1 mL of chloroform and dried to give 26 mg of the desired product (yield 72%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:9])=[N:4]1)[CH3:2].[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20][NH:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:9])[CH:6]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCn1nc(C)cc1N
Solvent: CCO
Product: CCOC(=O)C(=CNc1cc(C)nn1CC)C(=O)OCC

Procedure:
12.5 g of 1-ethyl-3-methyl-5-aminopyrazole (0.1 mol) and 21.6 g of ethoxymethylene malonic acid diethyl ester (0.1 mol) are heated to 120° (bath temperature) for 2 hours with stirring. The ethanol formed by this reaction is removed by means of a water aspirator. Vacuum distillation (b.p. 0.05 152°-153°) yields 24.0 g (81.5% of theory) of a quickly crystallizing oil, [[(1-ethyl-3-methyl-5-pyrazolyl)-amino]methylene]malonic acid diethyl ester, m.p. 60°-67°. The product, recrystallized from ligroin (90°-100°), melts at 69°-70°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]1([CH3:31])[C:23]([C:28](Cl)=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=1>C1(C)C=CC=CC=1>[CH3:31][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:29]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Yield: 79 %

Procedure:
1.0 g (0.00532 mol) of 1-benzyl-4-hydroxypiperidine and 0.72 ml (0.00532 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.7 ml (0.00532 mol) of o-toluoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:1). 1.3 g (80%) of 1-benzyl-piperidin-4-yl 2-methyl-benzoate were obtained as a brownish oil. MS: me/e (% basic peak)=309 (C20H23NO2+, 6), 232 (5.5), 173 (22.6), 119 (17.2), 91 (100), 82 (96).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH:11]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([F:20])=[C:15](Br)[C:14]=2[O:22][CH3:23])[CH3:12])[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][CH:35]=[C:36]([CH:39]=2)[C:37]#[N:38])O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH:11]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([F:20])=[C:15]([C:32]3[CH:33]=[N:34][CH:35]=[C:36]([C:37]#[N:38])[CH:39]=3)[C:14]=2[O:22][CH3:23])[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: COc1c(C(C)Nc2ncnc(N)c2C#N)cc(Cl)c(F)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C(C)Nc2ncnc(N)c2C#N)cc(Cl)c(F)c1-c1cncc(C#N)c1
Temperature: 90 °C
Yield: 37 %

Procedure:
Into a microwave vial was added 4-amino-6-{[1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]amino}pyrimidine-5-carbonitrile (8.0 mg, 0.020 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (5.51 mg, 0.0240 mmol), a solution of sodium carbonate (48 μL, 0.050 mmol) in water (48 μL), 1,4-dioxane (0.2 mL, 2 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol). The mixture was bubbled with N2 for 5 minutes and heated at 90° C. for 2 h. Purification by preparative LCMS (pH 10) gave the desired compound (37% yield). LCMS calculated for C20H16ClFN7O (M+H)+: m/z=424.1. found: 424.1.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:16]O)[N:6]2[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13].P(Br)(Br)[Br:19]>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:16][Br:19])[N:6]2[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)Cn1c(CO)nc2c(Cl)ncnc21
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(C)(C)Cn1c(CBr)nc2c(Cl)ncnc21

Procedure:
A solution of 6-chloro-8-hydroxymethyl-N9-neopentylpurine (1 mmol) in methylene chloride was treated with phosphorus tribromide (1 mmol) at 25° C. for 6 h. Extraction and chromatography afforded 6-chloro-8-bromomethyl-N9-neopentylpurine as a white solid. TLC: Rf=0.64, 25% EtOAc-hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:24])=[C:19]([S:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>>[Cl:24][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([N:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)[CH2:6][CH2:7]3)=[N:13][CH:14]=[N:15]2)=[CH:20][C:19]=1[S:22][CH3:23]
Reactant: Clc1ccc2c(c1)NCC2
Reactant: CSc1cc2c(Cl)ncnc2cc1Cl
Product: CSc1cc2c(N3CCc4ccc(Cl)cc43)ncnc2cc1Cl
Yield: 15 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 15% yield from 6-chloro-indoline and 4,7-dichloro-6-methylsulfanyl-quinazoline. (M.P. 167°-168° C.; LC-MS: 362 (MH+)).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].Br[CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1[nH]c2ccncc2c1Br
Reactant: CS(=O)(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(Br)c2cnccc2n1CCCS(C)(=O)=O
Temperature: 60 °C

Procedure:
A suspension of methyl 3-bromo-1H-pyrrolo[3,2-c]pyridine-2-carboxylate 12-c (1000 mg, 3.92 mmol), 1-bromo-3-(methylsulfonyl)propane 12-b (804 mg, 3.92 mmol) and cesium carbonate (1277 mg, 3.92 mmol) in dry DMF (8 ml) was heated at 60° C. for 2 hours. The reaction mixture was then cooled to room temperature and poured into iced water. The product was extracted three times with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by column chromatography using a gradient starting from 0% to 10% MeOH/DCM. After evaporation and drying in vacuo, 750 mg (2.0 mmol, 51.0%) of the target product 12-d was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.10-2.23 (m, 2H) 2.97 (s, 3H) 3.13-3.22 (m, 2H) 3.95 (s, 3H) 4.65 (t, J=7.28 Hz, 2H) 7.75 (dd, J=6.02, 1.00 Hz, 1H) 8.47 (d, J=6.02 Hz, 1H) 8.88 (d, J=1.00 Hz, 1H); m/z=375 (M+H)+, Br pattern.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[CH2:26]([O:28]C(C1C=CNC=1C)=O)C.COC1C=CC=CC=1CCl>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:28][CH3:26])[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: COc1ccccc1CCl
Product: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccccc1OC

Procedure:
Prepared similarly according to a reaction sequence in Example 117 steps (a), (b), (c) and (d) for the synthesis of 2,3-dibromo-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester starting from 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester, 2-methoxybenzyl chloride. The title compound, ESI MS (m/z): 483 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])([CH3:4])[CH3:3].[C:13](OC(=O)C)(=[O:15])[CH3:14]>ClCCl>[CH3:4][C:2]([N:5]([CH2:6][CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])[C:13](=[O:15])[CH3:14])([CH3:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)NCC(O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)N(CC(O)C(Cl)(Cl)Cl)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
To a stirred suspension of 5 grams of 3-(1,1-dimethylethylamino)-1,1,1-trichloro-2-propanol in 75 grams of dichloromethane at -60° C., 2.2 grams of acetic anhydride was added dropwise during 15 minutes. After the reaction mixture was allowed to warm to ambient temperature during 1 hour, the mixture was stirred for 2 hours. The solution was washed with 100 grams of saturated aqueous sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under a reduced pressure of 100 mm. Hg to 3.9 grams of an oil. The oil was crystallized from methylcyclohexane to yield 1.4 gram of white N-(1,1-dimethylethyl)-N-(3,3,3-trichloro-2-hydroxypropyl)acetamide melting 124°-126° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:17][CH3:18])[C:4]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7].[CH2:19]([SnH:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])/[CH:7]=[CH:6]/[CH2:5][C:4]([CH:3]([O:2][CH3:1])[O:17][CH3:18])([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:29][CH2:30][CH3:31]
Reactant: C#CCC(CCCC)(O[Si](C)(C)C)C(OC)OC
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)(O[Si](C)(C)C)C(OC)OC

Procedure:
A mixture of 10.0 g. (36.7 moles) of 4-dimethoxymethyl-4-trimethylsiloxy-1-octyne, 12.82 g. (44 moles) of tri-n-butylstannyl hydride and 100 mg. of azobisisobutyronitrile is heated to 140° C. under argon for 2 hours. The excess hydride is distilled off and the residue is purified by molecular distillation (bath temperature=170°-175° C., 0.2 mm.) to give 20.5 g. of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[C:27](=[O:31])([O:29][CH3:30])[NH2:28]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([NH:28][C:27](=[O:31])[O:29][CH3:30])=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: COC(N)=O
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Product: COC(=O)Nc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following the procedure of Example 61, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and methyl carbamate were coupled to give 149. MS: (ESI+) 443.1
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][N:5]=[CH:6][C:7]1[C:8]([F:30])=[C:9]([F:29])[C:10]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:11]([CH:19]=1)[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13].CON(C(C)=O)[C:34](=[O:36])[CH3:35]>CN(C)C=O.CO>[C:34]([NH:1][CH2:2][CH2:3][O:4][N:5]=[CH:6][C:7]1[C:8]([F:30])=[C:9]([F:29])[C:10]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:11]([CH:19]=1)[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13])(=[O:36])[CH3:35]
Reactant: NCCON=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: CON(C(C)=O)C(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)NCCON=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.8 %

Procedure:
To a solution of 5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (8.14 mg, 0.02 mmol) described in Example 22 in a mixture of dimethylformamide (1 ml) and methanol (5 ml), N-methoxy-diacetamide (100 mg, 0.76 mmol) was added, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was purified with Mega Bond Elut silica gel (5 g, Varian, Inc.). From the fractions eluted with 6% methanol/methylene chloride, 5-[(2-acetylamino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (8.10 mg, 92% yield) was obtained as a pale yellow solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:15])=[CH:9][C:8]=1[C:21]([F:24])([F:23])[F:22])#[N:6]>>[C:5]([C:7]1[CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[C:10]([NH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:15])=[CH:9][C:8]=1[C:21]([F:22])([F:24])[F:23])#[N:6]
Reactant: CCOC(=O)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Product: CCOC(=O)C(=O)Nc1cc(C(F)(F)F)c(C#N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To 75 ml ice-cooled 100% nitric acid was added gradually 7.25 g (25.3 mmol) 2-cyano-5-ethoxalylaminobenzotrifluoride. Stirring was continued at 25° C. for 3 h. The reaction mixture was poured into 500 ml ice-water to give a crude product. Recrystallization (ethanol-water) gave 5.1 g (61%) 2-cyano-5-ethoxalylamino-4-nitrobenzotrifluoride. M.p. 101°-102° C.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[C:5](=[S:10])([O:7][CH2:8][CH3:9])[S-:6].[K+]>C(O)C.O>[O:7]([CH2:8][CH3:9])[C:5]([S:10][CH2:2][C:3]#[N:4])=[S:6]
Reactant: N#CCBr
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=S)SCC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.7 %

Procedure:
A solution of bromoacetonitrile (12.4 g) and potassium O-ethyl dithiocarbonate (16.0 g) in ethanol (200 mL) were allowed to stir at room temperature for 16 hours. The reaction was diluted with water (100 mL) and the organics extracted with diethyl ether. The combined organic layers were washed twice with water, then brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue purified by column chromatography (silica-gel 60, 70-230 mesh) eluting with 4:6 ethyl acetate: petroleum spirit 40-60° C. to afford the title compound as a yellow oil (14.6 g, 90.7%). 1H-nmr (CDCl3) δ 1.48 (t, 3H); 3.88 (s, 2H); 4.72 (q, 2H). 13C-nmr (CDCl3) δ 13.7, 21.3, 71.5, 115.7, 209.2.
Reaction SMILES: FC1C=C([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[CH:9]=2)C=NC=1.[Cl:23]C1N=C(N2CCOC[C@@H]2C)C=C(C2C=NC=C(F)C=2)N=1.FC1C=C(NC(NCCO)=O)C=CC=1B1OC(C)(C)C(C)(C)O1>>[Cl:23][C:8]1[N:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[CH:9]=1
Reactant: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Reactant: C[C@H]1COCCN1c1cc(-c2cncc(F)c2)nc(Cl)n1
Agent: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2F)OC1(C)C
Product: CSc1nc(Cl)cc(N2CCOC[C@@H]2C)n1
Yield: 25 %

Procedure:
Method as described for intermediate 5 using (S)-4-(2-chloro-6-(5-fluoropyridin-3-yl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 7) and 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-hydroxyethyl)urea (intermediate 13). Material was purified by prep HPLC (high pH) to afford a brown solid, (4 1 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17](=[O:26])[C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:19](=[C:18]2/[C:17](=[O:26])[N:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:34][CH:33]=3)[C:27]3[C:32]/2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)cc1
Reactant: Clc1ccc(I)cc1
Product: COc1ccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3ccccc32)cc1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 3-phenyl-propynoic acid (4-methoxy-benzyl)-phenylamide. 1H NMR (300 Hz, CDCl3): δppm 3.77 (s, 3H), 4.88 (s, 2H), 6.53 (d, 1H), 6.67-6.71 (m, 2H), 6.80 (dd, 1H), 6.85-6.90 (m, 2H), 7.07 (t, 1H), 7.19-7.43 (m, 10H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]1.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.[Br:37]N1C(=O)CCC1=O.ClC1C=CC=CC=1>O>[Br:37][CH2:1][C:2]1[C:7]([O:8][CH:9]([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]1
Reactant: Cc1c(OC(F)F)cccc1-n1nnn(C)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: O
Solvent: Clc1ccccc1
Product: Cn1nnn(-c2cccc(OC(F)F)c2CBr)c1=O
Yield: 84.1 %

Procedure:
To a mixture of 1-(2-methyl-3-difluoromethoxyphenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 2) 1.0 g, 1,1′-azobis(cyclohexane-1-carbonitrile) 0.19 g, N-bromosuccinimide 0.80 g and chlorobenzene 50 ml was stirred with heating under reflux for eight hours. After cooling the mixture, to the reaction solutions was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(2-bromomethyl-3-difluoromethoxyphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 1.1 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:28]([NH:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.6) (0.404 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as an off-white solid (0.51 g, 88%). MS (ISP) 581.3 [(M+H)+]; mp 211° C.