Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(COC2C(C3N([CH2:17][C:18]4[CH:23]=[CH:22][C:21](CCC(O)=O)=[CH:20][CH:19]=4)C4C=C(F)C(F)=CC=4N=3)=CC=CN=2)CC1.[F:35][C:36]1[C:61]([F:62])=[CH:60][C:39]2[NH:40][C:41]([C:43]3[CH:59]=[CH:58][CH:57]=[CH:56][C:44]=3[CH2:45][O:46][C:47]3[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][C:48]=3[F:55])=[N:42][C:38]=2[CH:37]=1.BrCC1CCCCC1>>[CH:18]1([CH2:17][N:42]2[C:38]3[CH:37]=[C:36]([F:35])[C:61]([F:62])=[CH:60][C:39]=3[N:40]=[C:41]2[C:43]2[CH:59]=[CH:58][CH:57]=[CH:56][C:44]=2[CH2:45][O:46][C:47]2[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][C:48]=2[F:55])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Reactant: N#Cc1ccc(OCc2ccccc2-c2nc3cc(F)c(F)cc3[nH]2)c(F)c1
Agent: BrCC1CCCCC1
Product: N#Cc1ccc(OCc2ccccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)c(F)c1

Procedure:
The compound was prepared in analogy to Example 19, intermediate b, from 4-[2-(5,6-difluoro-1H-benzoimidazol-2-yl)-benzyloxy]-3-fluoro-benzonitrile and bromomethyl-cyclohexane (CAS Reg. No. 2550-36-9). Yellow powder (69%). MS (Turbo Spray): m/z=476.4 (M+H).
Reaction SMILES: [CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=3)[N:10]=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:44][CH2:45][C@@H:46]([OH:51])[C:47]([O:49][CH3:50])=[O:48].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH:44][CH2:45][C@@H:46]([OH:51])[C:47]([O:49][CH3:50])=[O:48])=[O:19])=[CH:15][CH:14]=3)[N:10]=[C:9]([C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@H](O)CN
Reactant: O=C(O)c1ccc(Cn2nc(-c3ccc(OC(F)(F)F)cc3)cc2C2CCCCC2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](O)CNC(=O)c1ccc(Cn2nc(-c3ccc(OC(F)(F)F)cc3)cc2C2CCCCC2)cc1

Procedure:
A solution of 44.4 mg product from Step D Example 1, 28.8 mg EDC, 20.3 mg HOBt, 31.1 mg methyl (2R)-3-amino-2-hydroxypropanoate hydrochloride from Step C above and 70 μL DIEA in 1 mL DMF was stirred at room temperature over night. The title compound was isolated by preparative HPLC using 55˜75% MeCN gradient over 10 minutes at 8.0 mL per minute with 0.1% TFA on a 9.4×250 mm SB-C18 Zorbax column as a white solid after lyophilization. LC-MS: 2.55 min. (M+H=546.3).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[N-:14]=[N+:15]=[N-:16].[Na+]>CC(C)=O>[N:14]([CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1)=[N+:15]=[N-:16]
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCc1nc2c(c(=O)[nH]1)COCC2
Temperature: 25 °C
Reaction time: 36 h
Yield: 90.2 %

Procedure:
To a solution of 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (20.6 g, 103 mmol) in acetone (513 mL) was added an aqueous solution of sodium azide (7.01 g, 108 mmol in 32 mL water). Reaction was stirred at room temperature for 36 h. Mixture was split into three equal volumes and each was diluted with dichloromethane (500 mL) and brine was added (100 mL) and the layers were separated. The aqueous fractions were combined and extracted with dichloromethane (5×100 mL). The combined organic layers were concentrated in vacuo. The resulting residue was taken up in dichloromethane (200 mL) and evaporated to dryness three times to yield 19.25 g of a yellow-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.59 (t, J=5.56 Hz, 2H) 3.85 (t, J=5.56 Hz, 2H) 4.28 (s, 2H) 4.36 (s, 2H) 12.58 (br. s., 1H)
Reaction SMILES: [I-].[CH3:2][C:3]1[N:10]2[C:6](=[N+:7]([CH3:15])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[S:5][CH:4]=1.[OH-:16].[Na+].O.[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([S:5]/[CH:4]=[C:3](/[N:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([CH3:15])[C:6]1=[O:16])\[CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:19]([S:5]/[CH:4]=[C:3](\[N:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([CH3:15])[C:6]1=[O:16])/[CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1csc2n1c1ccccc1[n+]2C
Reactant: [OH-]
Reactant: OCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: C/C(=C/SCc1ccccc1)n1c(=O)n(C)c2ccccc21
Product: C/C(=C\SCc1ccccc1)n1c(=O)n(C)c2ccccc21

Procedure:
Stage B 167 mg of 3,9-dimethyl[1,3]thiazolo[3,2-a]benzimidazol-9-ium iodide (0.51 mmol) and 162 mg of NaOH (8 eq) were solubilised in benzyl alcohol (5 mL) and the solution stirred under reflux. After 48 h water was added (20 mL) and the mixture extracted with CH2Cl2 (3×20 mL). The organic layer was dried with MgSO4 and evaporated under reduced pressure. The residue was then purified by chromatography on silica gel (eluent: CH2Cl2) to afford a mixture 55/45 of 1-[(1E)-1-(benzylsulfanyl)prop-1-en-2-yl]-3-methyl-1,3-dihydro-2H-benz imidazol-2-one and 1-[(1Z)-1-(benzyl sulfanyl)prop-1-en-2-yl]-3-methyl-1,3-dihydro-2H-benzimidazol-2-one isomers as a colourless oil (127 mg, 81% overall yield). HRMS m/z calcd C18H19N2OS [M+H]+: 311.1212; found: 311.1215 (analysis on the isomer mixture). The two isomers were separated by preparative TLC (eluent: CHCl3, eluted three times).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][OH:14])=[N:10][C:9]=2[C:15]([OH:17])=O)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.[F:40][C:41]1[C:56]([F:57])=[CH:55][C:44]2[NH:45][C:46]([CH2:48][CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][NH:50]3)=[N:47][C:43]=2[CH:42]=1>CN(C=O)C>[F:40][C:41]1[C:56]([F:57])=[CH:55][C:44]2[NH:45][C:46]([CH2:48][CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][N:50]3[C:15]([C:9]3[N:10]=[C:11]([CH2:13][OH:14])[S:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:17])=[N:47][C:43]=2[CH:42]=1
Reactant: O=C(O)c1nc(CO)sc1-c1ccc(F)cc1
Reactant: Fc1cc2nc(CC3CCCCN3)[nH]c2cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1nc(CO)sc1-c1ccc(F)cc1)N1CCCCC1Cc1nc2cc(F)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
A stirring solution of 5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazole-4-carboxylic acid (632 mg, 2.0 mmol, 80% pure), EDC.HCl (311 mg, 2.0 mmol) and 1-hydroxybenzotriazole (270 mg, 2.0 mmol) in DMF (20 ml) was treated with (RS)-5,6-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D18 (500 mg, 2.0 mmol). The reaction mixture was stirred at room temperature, under argon for 16 h. The DMF was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 0-10% methanol-ethyl acetate) afforded the title compound as a pale yellow solid (350 mg, 36%).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[C:10]([NH2:18])[C:11]([OH:17])=[CH:12][C:13]=32)[CH2:6]1)=O.[C:21]([Cl:26])(=O)[CH:22](C)[CH3:23]>>[ClH:26].[CH2:22]([C:23]1[O:17][C:11]2[C:10]([N:18]=1)=[CH:9][C:8]1[CH:7]3[CH2:16][CH:14]([CH2:15][NH:5][CH2:6]3)[C:13]=1[CH:12]=2)[CH3:21]
Reactant: Nc1cc2c(cc1O)C1CC2CN(C(=O)C(F)(F)F)C1
Reactant: CC(C)C(=O)Cl
Product: CCc1nc2cc3c(cc2o1)C1CNCC3C1
Product: Cl

Procedure:
2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-ethanone and isobutyryl chloride were converted to the title compound following the procedures described in Example 30 and Goldstein, S. W.: Dambek, P J J. Het. Chem. 1990, 27, 335. 1H NMR (400 MHz, CD3OD) δ 7.64 (s, 1H), 7.62 (s, 1H), 3.48 (d, J=2.5 Hz, 2H), 3.41 (d, J=12.0 Hz, 2H), 3.20 (2H), 3.01 (q, J=7.5 Hz, 2H), 2.45 (m, 1H), 2.17 (d, J=11.5 Hz, 1H), 1.42 (t, J=7.5 Hz, 3H). APCl MS m/e 229.2 [(M+1)+].
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Br:1][C:2]1[S:6][C:5]([CH2:7][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1ccc(CN2CCCC2)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 141.8 %

Procedure:
5-Bromo-2-thiophenecarbaldehyde (191 mg, 1.0 mmol) was diluted in a mixture of dichloromethane (6 mL) and N,N-dimethylformamide (2 mL), and cooled to 0° C. Pyrrolidine (107 mg, 1.5 mmol)) was added, followed by sodium triacetoxyborohydride (1.04 g, 4.9 mmol, 4.9 eq) and glacial acetic acid (2 drops). The reaction mixture was stirred at 23° C. for 2 h, then carefully quenched with saturated aq sodium bicarbonate (fizzing!). The reaction mixture was extracted with dichloromethane (2×10 mL), then the combined organic layers were filtered through a SCX cartridge (5 grams), eluting with methanol (10 mL). The first fraction was discarded if no product was present by tlc, and the desired product was eluted from the resin with methanol in ammonia (2M, Aldrich, 25 mL). The latter fraction was concentrated to afford 349 mg (>100%) of the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:34]=[CH:33][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([CH2:26][N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[CH:33][CH:34]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4].[N:27]1([CH2:26][C:25]2[CH:33]=[CH:34][C:22]([NH2:16])=[CH:23][CH:24]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Reactant: Brc1ccc(CN2CCOCC2)cc1
Product: CS(=O)(=O)c1ccc(-c2cccc3nc(Nc4ccc(CN5CCOCC5)cc4)nn23)cc1
Product: Nc1ccc(CN2CCOCC2)cc1
Yield: 176.6 %

Procedure:
[5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-ylmethyl-phenyl)-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (125 mg, 0.43 mmol) and 4-(4-bromobenzyl)morpholine (122 mg, 0.48 mmol) in a manner analogous to Example 77 to yield 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-ylmethyl-phenyl)-amine (73 mg, 37%) as an off-white powder following purification on a 4 g Isco silica gel column using methanol in dichloromethane (0-20%) as eluent. MP=222-223° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.66 (s, 1H), 8.32 (d, J=7.50 Hz, 2H), 8.15 (d, J=7.50 Hz, 2H), 7.66 (m, 4H), 7.30 (d, J=6.42 Hz, 1H), 7.20 (d, J=8.60 Hz, 2H), 3.55 (br s, 4H), 3.40-3.32 (m, 5H), 2.32 (br s, 4H). MS=465 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]([O:26]CC)=O.O.[NH2:30][NH2:31]>C(O)C>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]([NH:30][NH2:31])=[O:26]
Reactant: NN
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Solvent: O
Solvent: CCO
Product: NNC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Yield: 84.3 %

Procedure:
To a solution of ethyl (2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetate (0.35 g, 0.92 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.15 mL, 1.84 mmol) and the solution was heated at reflux for 16 h. Upon being allowed to cool to ambient temperature a solid precipitate formed. The solid was filtered and washed with ethanol (2 mL) to afford 2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetohydrazide (0.285 g, 84%) as a colorless solid: MS (ES+) m/z 367.9 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH2:27])(=[O:20])=[O:19])[CH2:9][CH2:8]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH:27][C:28](=[O:30])[CH3:29])(=[O:20])=[O:19])[CH2:11][CH2:12]1
Reactant: Nc1ccccc1S(=O)(=O)NCCCCN1CCN(c2ncccn2)CC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccccc1S(=O)(=O)NCCCCN1CCN(c2ncccn2)CC1

Procedure:
0.02 mol of N-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-2-aminobenzenesulphonamide and 0.5 mol of acetic anhydride are stirred at room temperature for 2 hours. The mixture is evaporated to dryness, concentrated aqueous ammonia solution is poured onto the residue and the base is extracted by shaking with methylene chloride. Purification is carried out by chromatography on silica gel; the eluting agent is CH2Cl2 /CH3OH (9:1). The substance is recrystallised from isopropanol.
Reaction SMILES: [C:1](=[O:43])([O:33][C:34]1C=CC([N+]([O-])=O)=C[CH:35]=1)[O:2][CH2:3][O:4][C:5]1[C:6](=[O:32])[C:7]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])=[O:21])=[CH:8][N:9]2[C:14]=1[C:13](=[O:15])[N:12]1[C@@H:16]([CH3:19])[CH2:17][O:18][C@@H:11]1[CH2:10]2.OCC[N:47]1[CH2:51][CH2:50][CH2:49][C:48]1=[O:52].C(N(CC)CC)C>CN(C1C=CN=CC=1)C>[C:1](=[O:43])([O:33][CH2:34][CH2:35][N:47]1[CH2:51][CH2:50][CH2:49][C:48]1=[O:52])[O:2][CH2:3][O:4][C:5]1[C:6](=[O:32])[C:7]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])=[O:21])=[CH:8][N:9]2[C:14]=1[C:13](=[O:15])[N:12]1[C@@H:16]([CH3:19])[CH2:17][O:18][C@@H:11]1[CH2:10]2
Reactant: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)Oc4ccc([N+](=O)[O-])cc4)c3C(=O)N12
Reactant: O=C1CCCN1CCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)OCCN4CCCC4=O)c3C(=O)N12

Procedure:
The title compound was prepared from {[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl 4-nitrophenyl carbonate (50 mg, 0.83 mmol), 1-(2-hydroxyethyl)-2-pyrrolidinone (9 μL, 0.083 mmol), triethylamine (35 μL, 0.250 mmol), and DMAP (10 mg, 0.083 mmol), in a process similar to that described in example 10. Purification by silica-gel chromatography and reverse-phase hplc afforded the title compound as a white solid. 1H NMR (CDCl3) δ 10.28 (m, 1H), 8.45 (s, 1H), 7.32 (m, 1H), 6.80 (m, 2H), 5.93 (d, J=6.8 Hz, 1H), 5.80 (d, J=6.4 Hz, 1H), 5.28 (dd, J=10, 3.6 Hz, 1H), 4.64-4.23 (m, 8H), 3.94 (m, 1H), 3.68-3.50 (m, 4H), 2.42 (t, J=8 Hz, 2H), 2.02 (m, 2H), 1.37 (d, J=6 Hz, 3H). ES+ MS: 591 (M+1).
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)CCC[CH2:12][CH2:11]1.CC(C)=[O:24]>>[C:1]1(=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:10][CH2:11][CH2:12][CH2:8]1
Reactant: CC(C)=O
Reactant: CC(C)c1ccccc1
Reactant: c1ccc(C2CCCCC2)cc1
Product: O=C1CCCCC1
Product: c1ccc(C2CCCCCCCCCCC2)cc1

Procedure:
Both the preparation of the starting material prepared by alkylation, e.g. cumene, cyclohexylbenzene (in the Hock process, cyclohexylbenzene gives not acetone but cyclohexanone) and cyclododecylbenzene (in the Hock process, cyclododecylbenzene gives cyclododecanone), and the acid-catalysed cleavage and rearrangement to phenol which follow the oxidation step generally proceed with high selectivity to give high yields.
Reaction SMILES: CNC(NC1SC(C2C=CN=CC=2)=C(C)N=1)=O.[CH3:18][C:19]1[N:20]=[C:21]([NH:36][C:37]([N:39]2[CH:43]=CN=C2)=[O:38])[S:22][C:23]=1[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:25]=1.[CH2:44]([C:46]1[O:50][C:49]([CH2:51]CN)=[N:48][CH:47]=1)[CH3:45]>>[CH2:44]([C:46]1[O:50][C:49]([CH2:51][CH2:43][NH:39][C:37]([NH:36][C:21]2[S:22][C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[N:25]=3)=[C:19]([CH3:18])[N:20]=2)=[O:38])=[N:48][CH:47]=1)[CH3:45]
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccnc(N2CCOCC2)n1
Reactant: CCc1cnc(CCN)o1
Agent: CNC(=O)Nc1nc(C)c(-c2ccncc2)s1
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3ccnc(N4CCOCC4)n3)s2)o1

Procedure:
The titled compound is prepared by an analogous procedure to 1-methyl-3-(4-methyl-5-pyridin-4-yl-thiazol-2-yl)-urea (example 18b) by replacing imidazole-1-carboxylic acid (4-methyl-5-pyridin-4-yl-thiazol-2-yl)-amide (example 18a) with imidazole-1-carboxylic acid [4-methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-yl]-amide (26a) and by replacing methylamine with 2-(5-ethyl-oxazol-2-yl)-ethylamine. The preparation of 2-(5-ethyl-oxazol-2-yl)-ethylamine is described in example 20d steps 1-4.
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[S:13][C:14]([C:18]([O:20]CC)=O)=[C:15]([CH3:17])[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].COC1C=C(C=CC=1OC)C([NH2:30])=O.ClC(C(C)=O)C(OCC)=O>C(O)CCC.C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[S:13][C:14]([C:18]([NH2:30])=[O:20])=[C:15]([CH3:17])[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCOC(=O)c1sc(-c2ccc(OC)c(OC)c2)nc1C
Reactant: COc1ccc(C(N)=O)cc1OC
Agent: CCOC(=O)C(Cl)C(C)=O
Agent: N
Solvent: CCO
Solvent: CCCCO
Product: COc1ccc(-c2nc(C)c(C(N)=O)s2)cc1OC
Reaction time: 168 h
Yield: 65 %

Procedure:
Into a mixed solution of 50 ml of aqueous 28% ammonia and 450 ml of ethanol, 15.4 g of ethyl 2-(3,4-dimethoxyphenyl)-4-methylthiazole-5carboxylate which had been prepared by heating a mixture of 3,4-dimethoxybenzamide, ethyl α-chloroacetoacetate and n-butyl alcohol under a reflux for 5 hours was dissolved, and the solution was left at room temperature for 7 days. After condensing the solution to solid under a reduced pressure, the thus obtained residue was recrystallized from an aqueous ethanolic solution to obtain the object as colourless minute aciculate melting at 218° to 219.5° C. in an amount of 9.0 g corresponding to the yield of 65%.
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1.C(O)C.[F:36][CH2:37][CH:38]1[CH2:40][O:39]1.C(N(CC)C(C)C)(C)C>O>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([CH2:40][CH:38]([OH:39])[CH2:37][F:36])[CH2:26][CH2:27]3)[N:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1
Reactant: FCC1CO1
Reactant: FC(F)c1nc2ccccc2n1-c1cc(N2CCOCC2)nc(NCC2CCNCC2)n1
Solvent: CCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: OC(CF)CN1CCC(CNc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-(piperidin-4-ylmethyl)pyrimidin-2-amine (100 mg) and ethanol (2 mL) were added 2-(fluoromethyl)oxirane (19 μL) and N,N-diisopropyl ethylamine (79 μL), and the mixture was stirred in a microwave reactor at 120° C. for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (ethyl acetate:hexane) to obtain 1-{4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]piperidin-1-yl}-3-fluoropropan-2-ol (81 mg) as a white powder.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C@H:17]2[CH2:21][CH2:20][CH2:19][O:18]2)=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].C(O)(=O)C(O)=O>C(O)C.C(O)(=O)C.[Pd].CC(O)C>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C@H:17]2[CH2:21][CH2:20][CH2:19][O:18]2)=[O:16])[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)[C@H]1CCCO1
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CC(=O)O
Solvent: CC(C)O
Product: O=C(NC1CCNCC1)[C@H]1CCCO1

Procedure:
(R)-Tetrahydro-furan-2-carboxylic acid (1-benzyl-piperidin-4-yl)-amide (128 g, 444 mmol) was dissolved in 300 mL ethanol and 50 mL acetic acid. Palladium on activated carbon (5 g) was added. A hydrogen pressure of 5 bars was applied, and hydrogenation was continued until no more hydrogen was consumed (about 5 days). The suspension was filtered through Celite, and the filtrate was evaporated to dryness under reduced pressure. The residue and oxalic acid (50 g, 555 mmol) were suspended in 500 mL 2-propanol and heated to dissolve the solids. Upon cooling, the oxalate salt of R-tetrahydro-furan-2-carboxylic acid piperidin-4-ylamide crystallized and was collected by filtration to yield (R)-Tetrahydro-furan-2-carboxylic acid piperidin-4-ylamide as an oxalate salt (99.0 g, 77%) as an off-white solid. 1H-NMR (300 MHz, DMSO-d6): δ 7.84 (d, J=7.8 Hz, 1H), 5.90 (bs, 2H), 4.18-4.14 (m, 1H), 3.89-3.67 (m, 3H), 3.25-3.20 (m, 2H), 2.94-2.71 (m, 2H), 2.13-2.00 (m, 1H), 1.56-1.58 (m, 6H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([O:15][CH2:16][C@@H:17]2[CH2:19][O:18]2)=[CH:4][CH:3]=1.NCC1CCN([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=2[S:36]([NH2:39])(=[O:38])=[O:37])CC1>>[Br:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([O:15][CH2:16][CH:17]([OH:18])[CH2:19][NH:13][CH2:12][CH:7]2[CH2:8][CH2:9][N:39]([S:36]([C:29]3[CH:28]=[CH:33][C:32]([O:34][CH3:35])=[CH:31][CH:30]=3)(=[O:37])=[O:38])[CH2:5][CH2:6]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(OC[C@@H]2CO2)c2c1[nH]c1ccccc12
Reactant: COc1ccc(S(N)(=O)=O)c(N2CCC(CN)CC2)c1
Product: COc1ccc(S(=O)(=O)N2CCC(CNCC(O)COc3ccc(Br)c4[nH]c5ccccc5c34)CC2)cc1
Yield: 77.4 %

Procedure:
Prepared from 1-bromo-4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.050 g, 0.15 mmol) and (4-aminomethyl-1-piperidinyl) 4-methoxybenzenesulfonamide (0.085 g, 0.3 mmol) of according to procedure used for Example 2 to give 0.035 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[NH2:14][C@H:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:16].Cl[CH:24]([CH3:28])[C:25](O)=[O:26]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:14]([C@H:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH3:16])[C:25](=[O:26])[CH:24]([CH3:28])[S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: C[C@H](N)C1CCCCC1
Reactant: CC(Cl)C(=O)O
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC(C)C(=O)N1[C@@H](C)C1CCCCC1

Procedure:
2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-amino-1-cyclohexylethane followed by α-chloropropionic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((1S)-1-cyclohexylethyl)-5-methyl-1,3-thiazolidin4-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33]>>[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CC(C)(C)CN
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Product: CC(C)(C)CNc1cccc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)c1

Procedure:
Compound is formed by reacting 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide with 2,2-dimethylpropylamine under conditions described in general procedure B. 1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.22 (m, 1H), 7.86 (m, 1H), 7.56 (m, 2H), 7.41 (d, 1H, J=8.4), 7.28 (s, 1H), 7.21 (d, 2H, J=5.7), 6.87 (m, 1H), 5.70 (m, 1H), 4.32 (t, 2H, J=5.7), 3.62 (t, 4H, J=4.8), 2.89 (t, 4H, J=5.4), 2.58 (t, 4H, J=4.8), 1.48(t, 1H, J=14.1), 0.97 (s, 9H). MS: 462.2 (M+1).