Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[C:17]([F:18])=[C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[C:17]([F:18])=[C:16]([N:19]([S:20]([CH3:23])(=[O:21])=[O:22])[CH3:25])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(NS(C)(=O)=O)c(F)c(C(=O)OCC)c1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)c(F)c(N(C)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
Dissolve 6-fluoro-5-methanesulfonylamino-N-methyl-N-propyl-isophthalamic acid ethyl ester (0.160 g, 0.444 mmol) in DMF (1.0 mL). Add potassium carbonate (44.4 mg, 0.32 mmol), iodomethane (41.5 μL, 0.67 mmol) and tetrabutylammonium bromide (14.3 mg, 0.04 mmol) to the solution. Stir the resulting slurry at room temperature for 16 h. Quench with saturated aqueous sodium sulfate solution (10 mL) and extract with ethyl acetate (3×30 mL). Combine the organic layers and dry (magnesium sulfate). Azeotrope the residue with xylenes to remove residual DMF. Purify (silica gel chromatography, eluting with 40:60 ethyl acetate:dichloromethane) to give the title compound as a solid (111 mg, 67%).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7]1)(=O)=O.[C:22]1([SH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([S:28][CH:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:7]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Sc1ccccc1
Reactant: CS(=O)(=O)OC1CCCN(C(=O)OCc2ccccc2)C1
Product: O=C(OCc1ccccc1)N1CCCC(Sc2ccccc2)C1

Procedure:
The entitled compound was produced according to the method of Example 1(1) but using benzyl 3-[(methylsulfonyl)oxy]piperidine-1-carboxylate produced according to the method described in a known reference (WO96/39407) and thiophenol.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH:26]=O)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:31]([NH:33][CH3:34])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:31]([N:33]([CH2:26][C:24]1[S:23][CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)[CH:25]=1)[CH3:34])[CH3:32]
Reactant: CCNC
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.8 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL) was added 2 drops of acetic acid, ethyl(methyl)amine (59 mg, 1.0 mmol), and stirred at room temperature for 5 h. To this was then added sodium triacetoxyborohydride (212 mg, 1.0 mmol) and reacted overnight. It was then purified by Gilson Preparatory HPLC to give 30.0 mg of the title compound (61.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[BH3-]C#[N:16].[Na+].[ClH:18]>CO>[ClH:18].[NH2:16][CH:8]1[CH2:7][CH2:6][CH2:5][C:4]2[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: COc1cccc2c1CCCC2=O
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cccc2c1CCCC2N
Yield: 79 %

Procedure:
50 mmol of 5-methoxy-1-tetralone, 0.5 mol of NH4OAc and 35 mmol of NaBH3CN are stirred in 150 ml of absolute MeOH at room temperature for 24 hours. The mixture is acidified to pH 2 with concentrated HCl and evaporated, the residue is taken up in 50 ml of H2O and the mixture is extracted by shaking 2-3×with ether. Any precipitates which arise are filtered off and combined with the H2O phase. The H2O phase is brought to pH 10 with solid KOH, saturated with NaCl and extracted by shaking 3×with ethyl acetate. After drying with Na2SO4, the organic phase is evaporated, the residue is dissolved in ether and the product is precipitated as the hydrochloride by passing the HCl. Yield: 79%; melting point: 250° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[S:23][C:22]4[C:17](=[N:18][CH:19]=[CH:20][C:21]=4[O:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][CH:35]5[CH2:37][CH2:36]5)=[O:33])=[CH:27][C:26]=4[F:38])[CH:16]=3)=[N:13][CH:14]=2)[CH2:4][CH2:3]1.[CH2:39]([O:41][C:42]([CH2:44][N:45]=[C:46]=[O:47])=[O:43])[CH3:40].CN(C=O)C>C1COCC1>[CH:35]1([NH:34][C:32](=[O:33])[NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][C:21]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:16]=[C:15]([C:12]5[N:13]=[CH:14][C:9]([CH2:8][N:5]6[CH2:6][CH2:7][CH:2]([NH:1][C:46](=[O:47])[NH:45][CH2:44][C:42]([O:41][CH2:39][CH3:40])=[O:43])[CH2:3][CH2:4]6)=[CH:10][CH:11]=5)[S:23][C:22]=34)=[C:26]([F:38])[CH:27]=2)[CH2:36][CH2:37]1
Reactant: NC1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Reactant: CCOC(=O)CN=C=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)NC1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 343 (106 mg, 0.20 mmol, scheme 71) in THF (3 mL) was added ethoxycarbonylmethyl isocyanate (0.068 mL, 0.6 mmol) and stirred at RT for 3 h. To the mixture was added DMF (2 mL) and stirred for 1 h. The mixture was then concentrated, water was added to form a precipitate that was collected by filtration, rinsed with water and purified via Biotage [linear gradient 2-20%, (methanol/dichloromethane; SiliaFlash 10 g cartridge]. Title compound 425 was obtained as a white solid (79.5 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.73 (s, 1H), 8.54 (brd, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.33 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.85 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.23-7.18 (m, 1H), 6.64 (d, J=5.2 Hz, 1H), 6.59 (bd, 1H), 6.15 (d, J=8.0 Hz, 1H), 6.06 (t, J=8.0 Hz, 1H), 4.06 (q, J=6.4 Hz, 2H), 3.74 (d, J=6.50 Hz, 2H), 3.54 (s, 2H), 2.77-2.66 (m, 2H), 2.58-2.51 (m, 2H), 2.13-2.04 (m, 2H), 1.78-1.70 (m, 2H), 1.40-1.30 (m, 2H), 1.18 (t, J=6.8 Hz, 3H), 0.68-0.62 (m, 2H), 0.45-0.40 (m, 2H). MS (m/z): 662.28 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:15]/[N+:12]([O-:14])=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(/C=C/[N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of 3-methyl-p-anisaldehyde (23.13 g, 154 mmol) and nitromethane (9.40 g, 154 mmol) in MeOH (260 ml) was cooled in an ice bath and treated dropwise with NaOH (162 ml of 1N solution; 162 mmol). The reaction mixture was stirred at rt for 1 hr. Water (50 ml) was then added and the mixture poured into 1N HCl (300 ml). The precipitate was collected and purified by flash chromatography on silica gel eluting with dichloromethane to provide methyl 2-methyl-4-[(E)-2-nitroethenyl]phenyl ether as a yellow solid (14.61 g; 49% yield).
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:19][CH:18]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COc1ccc(NN=C(Cl)C(C)=O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(NN=C(Sc2ccc(Cl)cc2)C(C)=O)cc1

Procedure:
A suspension of 31.7 g (0.139 mol) of 1-chloro-1-[(4-methoxyphenyl)hydrazono]-2-propanone in 400 ml of ethanol was treated with 23.4 g (0.161 mole) of 4-chlorothiophenol followed by 23.4 ml of triethylamine. The suspension was heated at reflux for 2 hours and cooled. The resultant suspension was filtered and the precipitate was washed with 1 portion of cold ethanol. The solids were dried in vacuo to yield 1-[(4-chlorophenyl)thio]-1-[(4-methoxyphenyl)hydrazono]-2-propanone, mp 111.5-113.5° C.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH:22](O)[C:23]([F:41])([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:29]=3)C(O)=O)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.O>N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH:22]=[C:23]([F:41])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:29]=3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: O=C(O)C(F)(Cc1cccc(Oc2ccccc2)c1)C(O)C1(c2ccc(Cl)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: FC(=CC1(c2ccc(Cl)cc2)CC1)Cc1cccc(Oc2ccccc2)c1
Temperature: 60 °C
Yield: 100 %

Procedure:
p-Toluenesulfonyl chloride (19.07 mg, 0.10 mmol) is added to a solution of 1-(p-chlorophenyl)-α-fluoro-β-hydroxy-α-(m-phenoxybenzyl)cyclopropanepropionic acid having a 9:1 [R,S and S,R] to [R,R and S,S] ratio (20 mg, 0.05 mmol) in pyridine (2 mL). The reaction mixture is heated to 60° C. and poured into water. The aqueous mixture is extracted with diethyl ether. The organic extracts are combined, washed sequentially with 2 N hydrochloric acid, water, 10% sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a colorless oil (18 mg, 100%) which is found to have a 9:1 Z to E ratio by NMR spectral analyses.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C@@H:6]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7][C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][C@@H:19]([C:28](O)=[O:29])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:42]([S:61][CH2:62][C@@H:63]([C:65]([NH2:67])=[O:66])[NH2:64])([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:41])[C@@H:6]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][C@@H:19]([C:28]([NH:64][C@H:63]([C:65]([NH2:67])=[O:66])[CH2:62][S:61][C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:29])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])=[CH:31][CH:32]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
1.20 g (2.07 mmol) of the compound from example 9A was dissolved in 48 ml dichloromethane. 0.750 g (2.07 mmol) S-Trityl-L-cysteinamide, 0.36 ml (2.07 mmol) N,N-diisopropylethylamine and 0.787 g (2.07 mmol) HATU were added. The reaction mixture was split into 3 portions. The portions were heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 400 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 1.30 g (1.5 mmol, 56% of theory, 82% purity) of the desired product.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[N:22]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:35][N:36]([CH3:56])[CH2:37][CH2:38][O:39][CH:40]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1>ClCCl>[CH2:1]([C:5]1[N:6]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:45](=[O:46])[C:44]2[CH:43]=[CH:42][C:41]([CH:40]([O:39][CH2:38][CH2:37][N:36]([CH3:35])[CH3:56])[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:49][CH:48]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:8]=2[N:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCN
Reactant: CN(C)CCOC(c1ccccc1)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCNC(=O)c1ccc(C(OCCN(C)C)c2ccccc2)cc1
Reaction time: 16 h
Yield: 47.2 %

Procedure:
Under a nitrogen atmosphere, 4-(2-butyl-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butan-1-amine (122 mg, 0.33 mmol) was dissolved in dichloromethane and triethylamine (0.093 mL, 0.67 mmol). The solution was cooled in an ice-water bath and 4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzoyl chloride (106 mg, 0.33 mmol) was dissolved/slurried in dichloromethane and added dropwise. The ice bath was removed and the reaction was stirred for an additional 16 hours. The reaction was quenched with 10% aqueous sodium carbonate. The phases were separated and the aqueous fraction was extracted with dichloromethane. The organic fractions were combined, washed with water followed by brine, dried (Na2SO4), decanted and evaporated to yield a yellow oil. Purification by flash column chromatography (silica gel, 92:8 dichloromethane/methanol gradient to 95:5 dichloromethane/methanol) provided 101 mg of N-[4-(2-butyl-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzamide as a pale yellow solid. The product was determined to be 97+% pure by HPLC.
Reaction SMILES: [CH:1]([N:3]1[CH:12]([C:13](O)=O)[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=O.[C:16]1(=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[CH:18]=C1>C(OC(=O)C)(=O)C>[CH:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][C:12]1[N:3]([CH:1]=[C:18]3[C:13]=1[C:16](=[O:27])[C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:19]3=[O:26])[CH2:4]2
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: O=CN1Cc2ccccc2CC1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1c2ccccc2C(=O)c2c1cn1c2Cc2ccccc2C1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-formyl-3-carboxy-1,2,3,4-tetrahydroisoquinoline (20 g) and 1,4-naphthoquinone (30.8 g) in acetic anhydride (500 ml) was heated at 100° C. with stirring for 30 minutes. The reaction mixture was cooled, the solid collected by filtration, washed with acetic anhydride (50 g) with ether (2×100ml) and dried to give the title compound in Form B (26 g).
Reaction SMILES: IC.[NH:3]1[C:7]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[N:6][N:5]=[N:4]1.[C:35](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:35][N:6]1[C:7]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[CH:26]=4)=[O:23])=[CH:19][CH:20]=3)[CH:11]=[CH:10][N:9]=2)=[N:3][N:4]=[N:5]1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ccc(Oc2ccnc(-c3nnn[nH]3)c2)cc1)Nc1cccc(C(F)(F)F)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnnc1-c1cc(Oc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)ccn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Iodomethane (0.21 mL, 3.40 mmol, 1.5 equiv) is added to a cold (0° C.) mixture of 1-{4-[2-(1H-tetrazol-5yl)-pyridin-4-yloxy]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea (Example 122) (1.0 g, 2.27 mmol) and potassium carbonate (0.94 g, 6.80 mmol, 3.0 equiv) in DMF abs. (5.8 mL), under an argon atmosphere. The reaction mixture is stirred at 0° C. for 2 h, allowed to warm to rt and stirred for additional 20 h. The resulting brown suspension is filtered and concentrated in vacuo. MeOH (10 mL) and DMF (0.5 mL) are added to the residue and the resulting suspension is filtered. The white solid is washed with MeOH and dried in vacuo to afford the title compound as a white solid. The filtrate is concentrated in vacuo and the residue is purified by MPLC (CH3CN/H2O/TFA) to afford additional title compound as a beige solid: ES-MS: 455.9 [M+H]+; single peak at tR=9.15 min (System 2).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([N:20]3[CH2:24][CH:23]([CH2:25][NH2:26])[O:22][C:21]3=[O:27])=[CH:17][CH:18]=2)[CH2:13][CH:12]1[CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:37](=[O:39])[CH3:38])[O:22][C:21]3=[O:27])=[CH:17][CH:18]=2)[CH2:13][CH:12]1[CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OCC1Cc2cc(N3CC(CN)OC3=O)ccc2N1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC(CO[Si](C)(C)C(C)(C)C)N3C(=O)OCc2ccccc2)C(=O)O1
Temperature: 0 °C

Procedure:
An ice cold, stirred mixture of the product from Step 7 (6.39 g, 0.0125 mol) and pyridine (75 ml), under nitrogen is treated, dropwise during 10 min, with acetic anhydride (24 ml). The mixture is kept in the ice bath for 20 min and at ambient temperature for 2 h. It is then concentrated in vacuo. The residue is mixed with ethyl acetate, washed with dilute sodium bicarbonate, water, and brine, dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel with mixtures of MeOH—CH2Cl2 containing 2.5 −5% MeOH gave the titled product: MS (ES) m/z 554 (M+H+), 576 (M+Na+); 1H NMR (300 MHz, CDCl3) δ−0.12 (s, 3H), −0.07 (s, 3H), 0.75 (s, 9H), 2.01 (s, 3H), 3.08 (m, 1H), 3.23 (m, 1H), 3.58 (m, 2H), 3.73 (m, 3H), 4.00 (m, 1H), 4.50 (broad s, 1H), 4.73 (m, 1H), 5.27 (m, 2H), 6.22 (broad s, 1H), 7.08 (m, 1H), 7.37 (m, 6H), 7.79 (broad s, 1H).
Reaction SMILES: [N:1]1[C:11]2[C:10]3[S:12][C:13]([CH:15](Br)[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=O)=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:26][C:27]([NH2:29])=[S:28].C(O)C>>[N:1]1[C:11]2[C:10]3[S:12][C:13]([C:15]4[N:26]=[C:27]([NH2:29])[S:28][C:16]=4[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC(N)=S
Reactant: O=C(c1ccccc1Cl)C(Br)c1cc2c(s1)-c1ncccc1OCC2
Solvent: CCO
Product: Nc1nc(-c2cc3c(s2)-c2ncccc2OCC3)c(-c2ccccc2Cl)s1

Procedure:
6,7-Dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl-(2-chlorophenyl)-2-bromoethanone from Example 37 (100.0 mg, 0.230 mmol) and thiourea (20.14 mg, 0.264 mmol) were heated in ethanol (5 mL, 80 mmol) for 1 hour. The solvent was evaporated to half of the volume, whereupon the product crystallized upon standing. The product 165 was collected by filtration and washed with cold ethanol (yield 43 mg, 45%). 1H NMR (400 MHz, DMSO) δ 8.15 (d, J=3.2, 11H), 7.66 (d, J=8.2, 1H), 7.54 (t, J=7.6, 2H), 7.47 (t, J=7.4, 1H), 7.36 (d, J=8.1, 1H), 7.16 (dd, J=4.5, 8.1, 1H), 6.73 (s, 1H), 5.80-4.90 (m, 2H), 4.24 (t, J=4.7, 2H), 3.04 (t, J=4.7, 2H). MS (ESI+) 412.1
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][CH:37]([NH:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH3:38]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:43][CH2:42][CH2:41][CH2:40][NH:39][CH:37]([CH3:38])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CC(C)NCCCN
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(NCCCNC(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 68 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) was added N-(1-methylethyl)-1,3-propanediamine (0.025 mL, 0.179 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (15 mg, 68%). LC-MS m/z 554 (M+H)+; 1H-NMR (MeOD) δ 1.00 (d, 6H), 1.27 (d, 6H), 1.60 (m, 2H), 2.31 (s, 3H), 2.50 (m, 2H), 2.75 (m, 1H), 3.15 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][C:32](=[O:36])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([N:33]2[CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH2:31][C:32]2=[O:36])[CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CC(C1CCN(C(=O)OCc2ccccc2)CC1)N1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.9 %

Procedure:
To a solution of methyl 3-(1-benzyloxycarbonylpiperidin-4-yl)acrylate (5.55 g) and 4-(tert-butoxycarbonyl)-2-piperazinone (3.66 g) in tetrahydrofuran (50 ml) was added potassium tert-butoxide (0.56 g), and the mixture was stirred under nitrogen atmosphere at room temperature for 3 days. The reaction solution was diluted with ethyl acetate (50 ml), washed with 0.5N hydrochloric acid and saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (eluent:acetone/hexane=1/2) to give colorless amorphous of methyl 3-(1-benzyloxycarbonylpiperidin-4-yl)-3-[4-(tert-butoxycarbonyl)-2-oxopiperazine-1-yl]propionate (5.51 g).