Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.CN([CH:15]=[O:16])C.O=P(Cl)(Cl)Cl.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([CH:15]=[O:16])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CN(C)C=O
Reactant: COc1cc(F)cc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(F)cc(OC)c1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A cooled (−5° C.) mixture of commercially available 1-fluoro-3,5-dimethoxybenzene (500 mg; 3.20 mmol; 1.0 equiv.) and DMF (4.680 g; 64.03 mmol; 20.0 equiv.) was treated dropwise with POCl3 (2.454 g; 16.01 mmol; 5.0 equiv.). This mixture was further stirred at rt for 1.5 h, and was then heated to 60° C. for 3 h. After cooling to rt, ice-water (50 ml) and a solution of 2.5 M aq. NaOH (24 ml) were successively added. After extractions with AcOEt (3×30 ml), the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=1/1) afforded 4-fluoro-2,6-dimethoxybenzaldehyde as a yellow solid. LC-MS (conditions A): tR=0.50 min.; [M+H]+: 185.10 g/mol. According to 1H-NMR (CDCl3; 400 MHz), this product also contained 19% of the regioisomer 2-fluoro-4,6-dimethoxybenzaldehyde. This minor regioisomer could be advantageously removed after further chemical transformations of the isomeric mixture.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.Cl.[CH3:13][O:14][C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[N:21][CH:22]=1)=[O:16].Cl.C(=O)([O-])[O-].[K+].[K+]>>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:19]2[CH:20]=[N:21][CH:22]=[C:17]([CH:18]=2)[C:15]([O:14][CH3:13])=[O:16])=[CH:6][CH:5]=1
Reactant: FC(F)Oc1ccc(Br)cc1
Reactant: COC(=O)c1cncc(B(O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cncc(-c2ccc(OC(F)F)cc2)c1

Procedure:
10.0 g (44.8 mmol) of 4-(difluoromethoxy)bromobenzene were reacted according to General Method 3A with 14.6 g (67.3 mmol) of [5-(methoxycarbonyl)pyridin-3-yl]boronic acid hydrochloride. The release of the hydrochloride was achieved by additional addition of 6.80 g (49.3 mmol) of potassium carbonate. Yield: 8.6 g (67% of theory)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].O1[CH2:33][CH2:32]OCC1>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>[C:11]([C:10]1[CH:9]=[C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[CH:3]=2)[CH:4]=[CH:32][CH:33]=1)#[N:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Br)c2)CC1
Reactant: C1COCCO1
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: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(-c3cccc(C#N)c3)c2)CC1
Temperature: 130 °C
Yield: 86 %

Procedure:
To 1,1-dimethylethyl 4-[(3-bromophenyl)methylidene]-1-piperidinecarboxylate (2.11 g, 5.99 mmol) in 1,4-dioxane (30 mL) and water (10.00 mL) was added m-NC(C6H4)B(OH)2 (1.056 g, 7.19 mmol), Pd(Ph3P)4 0.277 g, 0.240 mmol), K2CO3 (2.483 g, 17.97 mmol). The resulting mixture was split into two equal portions and each portion was heated in a microwave at about 130° C. for about 15 min. The reaction mixture was evaporated using a Glas-Col evaporator and purified with CombiFlash chomatograph to afford the title compound (1.93 g, 86%). LC-MS m/z 749 (2M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][CH2:10][CH:9]2[NH2:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:11][CH2:10][C@H:9]2[NH:12][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[C:21]([F:20])([F:31])[F:32])=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: NC1CCC1c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CC[C@@H]1c1ccc(Cl)cc1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
To a solution of 2-(4-chlorophenyl)cyclobutanamine (105 mg, 0.55 mmol) and triethylamine (140 mg 2.5 eq.) in THF was added 2-trifluoromethyl-benzoylchloride (127.46 mg, 1.1 eq.) at 0° C. The RM was stirred at rt for 2 h. Et3N.HCl was filtered off and the THF was evaporated. The residue—mixture of two isomers cis and trans (2:1) was purified and separated with chromatography on silica gel, eluent i-Hx:diethylether 1:1, (KMnO4 stain). N-[cis-2-(4-chlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide (cis) (33 mg, m.p. 147-9° C.) and its trans isomer (17 mg, m.p. 117-9° C.) were isolated as crystalline products.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([NH:12][C@H:13]([C:18]([OH:20])=O)[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:36]([N:38]([C:41]1[CH:46]=[CH:45][C:44]([CH2:47][N:48]([NH2:72])[CH2:49][C@H:50]([OH:71])[C@@H:51]([NH:59][C:60](=[O:70])[C@H:61]([CH:67]([CH3:69])[CH3:68])[NH:62][C:63]([O:65][CH3:66])=[O:64])[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:43][CH:42]=1)[CH2:39][CH3:40])[CH3:37]>CN(C=O)C>[CH2:36]([N:38]([C:41]1[CH:46]=[CH:45][C:44]([CH2:47][N:48]([NH:72][C:18](=[O:20])[C@H:13]([C:14]([CH3:15])([CH3:16])[CH3:17])[NH:12][C:10]([O:9][CH3:8])=[O:11])[CH2:49][C@H:50]([OH:71])[C@@H:51]([NH:59][C:60](=[O:70])[C@H:61]([CH:67]([CH3:68])[CH3:69])[NH:62][C:63]([O:65][CH3:66])=[O:64])[CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)=[CH:43][CH:42]=1)[CH2:39][CH3:40])[CH3:37]
Reactant: CCN(CC)c1ccc(CN(N)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](NC(=O)OC)C(C)C)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(CN(C[C@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](NC(=O)OC)C(C)C)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In analogy with Example 2, 1.05 ml (7.5 mmol) of triethylamine are added to a solution of 0.37 g (2 mmol) of N-methoxycarbonyl-(L)-tert-leucine (Example 2h), 0.7 g (3.75 mmol) of EDC and 0.33 g (2.5 mmol) of HOBT in 8 ml of DMF and the whole is stirred at RT for 10 min. After that, 0.95 g (1.25 mmol) of 1-[p-(N,N-diethylamino)phenyl]-4(S)-hydroxy-2-amino-5(S)-[N-(N-methoxycarbonyl-(L)-valyl)amino]-6-phenyl-2-azahexane hydrochloride (Example 5b), dissolved in 2 ml of DMF, is added and the whole is stirred at RT for 2.75 h. The reaction mixture is evaporated under reduced pressure. After having been taken up in methylene chloride, the residue is washed consecutively with water, aqueous sodium bicarbonate and brine. The organic phase is then concentrated and the residue is digested in DIPE. The title compound is obtained after filtering off and drying.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][NH2:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:38][CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=1)=[O:29]
Reactant: O=C(Br)CBr
Reactant: NCc1ccccn1
Reactant: COc1ccc(CC2NCCc3c(OC)ccc(OC)c32)cc1OC
Product: COc1ccc(CC2c3c(OC)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-picolylamine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][C@H:15]3[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]3)[C:7]=2[CH:29]=1.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([CH2:14][CH2:13][N:8]2[C:7]3[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[O:11][CH2:10][C:9]2=[O:12])[CH2:16][CH2:17]1
Reactant: COc1ccc2c(c1)N(CC[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)C(=O)CO2
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: COc1ccc2c(c1)N(CC[C@H]1CC[C@H](N)CC1)C(=O)CO2

Procedure:
tert-Butyl {trans-4-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]cyclohexyl}carbamate (Intermediate 75) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([CH3:14])=[C:12]([CH2:15]O)[S:11][C:10]=2[CH:17]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([CH3:14])=[C:12]([CH2:15][Cl:3])[S:11][C:10]=2[CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)sc2cc(Br)ccc12
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1c(CCl)sc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (2.0 ml) was added dropwise to a stirred solution of 6-bromo-2-hydroxymethyl-3-methylbenzo[b]thiophene (3.60 g) and pyridine (3 drops) in chloroform (80 ml). The solution was stirred at room temperature for 1 hour, then washed with water, sodium bicarbonate solution and dried (Na2SO4). Evaporation of the solvent gave a quantitative yield of 6-bromo-2-chloromethyl-3-methylbenzo[b]thiophene. A sample crystallised from petrol (b.p. 40°-60°) had m.p. 92°-93°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:26])[N:11]([O:22][CH2:23][O:24][CH3:25])[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[OH:14].C(N(CC)CC)C.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:38]([O:37][C:35](=[O:36])[O:14][C:13]1[C:12]2([CH2:15][CH2:16][N:17]([O:20][CH3:21])[CH2:18][CH2:19]2)[N:11]([O:22][CH2:23][O:24][CH3:25])[C:10](=[O:26])[C:9]=1[C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:39]
Reactant: CCOC(=O)Cl
Reactant: COCON1C(=O)C(c2cc(C)ccc2C)=C(O)C12CCN(OC)CC2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)N(OCOC)C12CCN(OC)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-methoxymethoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (9.0 g, 24.83 mmol), triethylamine (6.9 ml, 5.0 g, 49.66 mmol) and 4-dimethylaminopyridine (100 mg, 0.82 mmol) in tetrahydrofuran (250 ml) at 0° C. was added a solution of ethyl chloroformate (3.09 ml, 3.5 g, 32.28 mmol) in tetrahydrofuran (20 ml) dropwise. The suspension was stirred at 0° C. for one hour, and at room temperature for one hour. The reaction mixture was evaporated, diluted with ethyl acetate and filtered to remove salts. The filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution (2×100 ml) and brine, dried over sodium sulfate and concentrated. The oily residue was purified by chromatography on silica gel (ethyl acetate/hexane 1:1). Yield: 9.63 g of carbonic acid 3-(2,5-dimethyl-phenyl)-8-methoxy-1-methoxy-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester ethyl ester (title compound P1ii.2) as a white solid, mp 109-111° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([O:22][CH3:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24]N1C(=O)CCC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([O:22][CH3:23])=[C:14]([Cl:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Product: COc1nc2c(cc1Cl)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 5, intermediate from (4R,9aR)-6-methoxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and N-chlorosuccinimide.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].N12CCCN=C1CCCCC2.[I-].[Na+].[SH:40][CH2:41][CH2:42][CH2:43][OH:44]>C(O)CCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][S:40][CH2:41][CH2:42][CH2:43][OH:44])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCCl)ccc1Cl
Reactant: OCCCS
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCSCCCO)ccc1Cl
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-5-[3-chloropropoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.06 g, Example 3a) and 1,8-diazabicyclo(5.4.0)undec-7-ene (0.07 ml) in 1-butanol (5 ml) was added sodium iodide (0.023 g) and 3-mecaptopropan-1-ol (0.04 ml). The reaction vessel was sealed and the mixture heated at 100° C. for 24 h. The reaction mixture was diluted with ethyl acetate and washed twice with 2M hydrochloric acid, twice with sodium hydrogencarbonate solution and once with brine. The organics were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by NPHPLC (eluting with 0-2% ethanol in dichloromethane) to leave the title compound as a white solid (0.05 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[Br-].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH2:36][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:28]1.C(=O)([O-])[O-].[K+].[K+]>O.CS(C)=O>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[CH:6]/[C:5]2[CH:8]=[CH:9][C:2]([N:17]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:16][CH2:15][O:14][CH3:13])=[CH:3][C:4]=2[N+:10]([O-:12])=[O:11])=[N:28]1
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: COCCNCCN1CCOCC1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COCCN(CCN1CCOCC1)c1ccc(/C=C/c2n[nH]c3ccccc23)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 16.1 %

Procedure:
4-Fluoro-2-nitrobenzaldehyde (0.20 g, 1.2 mmol), N-(2-methoxyethyl)-2-morpholinoethylamine (1.2 g, 6.5 mmol) and DMSO (3.5 mL) were added and stirred at 100° C. for 3 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 to ethyl acetate). In a similar manner to Example 1, the obtained 4-[N-(2-methoxyethyl)-N-(2-morpholinoethyl)amino]-2-nitrobenzaldehyde was dissolved in methanol (8.0 mL) and the solution was added with (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.21 g, 0.62 mmol) and potassium carbonate (0.17 g, 1.3 mmol) followed by stirring at room temperature for 1 hour. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=9/1) to obtain (E)-N-{4-[2-(1H-indazol-3-yl)vinyl]-3-nitrophenyl}-N-(2-methoxyethyl)-2-morpholinoethylamine (45 mg, 20%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[OH-].[Na+].O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17]Cl)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[CH:12][CH:11]=1
Reactant: CC(O)CN
Reactant: ClCCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)CNCCc1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
In a 500-mL round-bottom flask equipped with magnetic stirring, a thermocouple, a condenser, and a nitrogen bubbler vented to a caustic scrubber, 1-aminopropan-2-ol (60.2 g, 802 mmol) was heated to 120° C. The solution of 1-chloro-4-(2-chloroethyl)benzene in toluene prepared in Step A was added dropwise over 70 min at 114° C. to 120° C. and upon completion of the addition, the mixture was stirred at reflux for a further 2 h and then allowed to cool to 72° C. Aqueous NaOH (50%, 12.83 g, 160 mmol) and water (25 mL) were added and the mixture was stirred at 70 to 73° C. for approximately 5 minutes. The phases were allowed to separate, the aqueous phase was removed, and the organic phase washed at 80° C. (bath) for approximately 5 min with water (4×25 mL). The combined aqueous phases were extracted with toluene (37 mL) at 80° C. (bath). The combined organic phases were concentrated under reduced pressure at 60° C. (bath) and then at room temperature overnight to leave the title compound as a white solid.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1.Cl.[N+](C1C=CC([C:27]2[CH:35]=[C:34]([NH:36][C:37]([NH2:39])=[NH:38])[CH:33]=[CH:32][C:28]=2[C:29](O)=[O:30])=CC=1)([O-])=O.C(N(CC)CC)C>CN(C)C=O>[ClH:1].[NH:36]([C:34]1[CH:35]=[CH:27][C:28]([C:29]([NH:2][CH2:3][CH2:4][C:5]2[CH:16]=[CH:15][C:8]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=2)=[O:30])=[CH:32][CH:33]=1)[C:37]([NH2:39])=[NH:38]
Reactant: N=C(N)Nc1ccc(C(=O)O)c(-c2ccc([N+](=O)[O-])cc2)c1
Reactant: COC(=O)CCc1ccc(CCN)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(CCNC(=O)c2ccc(NC(=N)N)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.4 %

Procedure:
A mixture of 486 mg of methyl 4-(2-aminoethyl)hydrocinnamate hydrochloride, 672 mg of 4-nitrophenyl-4-guanidino-benzoate hydrochloride, 404 mg of triethylamine and 10 ml of dimethylformamide was stirred at room temperature under argon for 5 hours. The reaction mixture was then evaporated to dryness in vacuo, and the residue was chromatographed on 25 g of MCI gel. 520 mg of amorphous methyl p-[2-(p-guanidinobenzamido)ethyl]hydrocinnamate hydrochloride were obtained. IR bands (KBr) at 3339, 3187, 1727, 1678, 1644, 1579, 1500, 1289, 1107, 852 cm-1.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4](OC)=[O:5].C(Cl)Cl>CO>[OH:5][CH2:4][C:3]1[C:2]([CH3:1])=[N:11][CH:10]=[CH:9][C:8]=1[C:12]([F:15])([F:13])[F:14]
Reactant: COC(=O)c1c(C(F)(F)F)ccnc1C
Solvent: ClCCl
Solvent: CO
Product: Cc1nccc(C(F)(F)F)c1CO

Procedure:
Methyl 2-methyl-4-trifluoromethylnicotinate was reduced using the procedure as given in step 1 of Example 3. 3-Hydroxymethyl-2-methyl-4-trifluoromethylpyridine was obtained as a pale yellow waxy solid(TLC Rf = 0.31 (97:3 CH2Cl2 :MeOH)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[CH3:26][O:27][CH2:28][CH2:29][O:30][C:31]1[CH:32]=[C:33]([NH:41][C:42](=O)[O:43]C2C=CC=CC=2)[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([NH:22][C:42]([NH:41][C:33]2[CH:34]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:36]=[C:31]([O:30][CH2:29][CH2:28][O:27][CH3:26])[CH:32]=2)=[O:43])[CH:23]=[CH:24][CH:25]=1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Solvent: CO
Solvent: ClCCl
Product: COCCOc1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OCCOC)c(OC)cc34)c2)cc(C(F)(F)F)c1
Yield: 76 %

Procedure:
3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from the previous step (102 mg, 0.3 mmol) was reacted with phenyl 3-(2-methoxyethoxy)-5-(trifluoromethyl)phenylcarbamate from Example 117A (160 mg, 0.45 mmol) in the manner described in Example 115C. The final product was purified by column chromatography (25-100% EtOAc/hexanes then 5-10% MeOH/DCM) to give 1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)urea (137 mg, 0.23 mmol, 76%). 1H NMR (300 MHz, DMSO-d6) δ 9.10 (s, 1H), 9.04 (s, 1H), 8.56 (s, 1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.49 (s, 1H), 7.45-7.38 (m, 2H), 7.32-7.26 (m, 2H), 6.96 (d, 1H), 6.87 (s, 1H), 4.37-4.31 (m, 2H), 4.19-4.12 (m, 2H), 4.00 (s, 3H), 3.80-3.73 (m, 2H), 3.70-3.63 (m, 2H), 3.36 (s, 3H), 3.31 (s, 3H); LC-MS (ESI) m/z 603 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[Br:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[CH:21]=[CH:22][CH2:23]Br.C(OC(C)C)(C)C>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:23][CH:22]=[CH:21][C:20]3[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=3[Br:18])[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: BrCC=Cc1ccccc1Br
Reactant: Nc1nc2c(s1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: Nc1nc2c(s1)CCN(CC=Cc1ccccc1Br)CC2
Yield: 42 %

Procedure:
Prepared analogously to Example 1 from 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, potassium carbonate and 2-bromo-cinnamyl bromide in anhydrous dimethylformamide for 2 hours at 20° C. Yield: 42% of theory, Melting point: 103°-106° C. (diisopropylether).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[CH:11]=[CH:10][N:9]=1>C(O)CCC>[ClH:7].[CH2:15]([O:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:13]=1)[CH3:16]
Reactant: C1CNCCN1
Reactant: CCOc1ccnc(Cl)c1
Solvent: CCCCO
Product: CCOc1ccnc(N2CCNCC2)c1
Product: Cl
Temperature: 115 °C
Reaction time: 36 h
Yield: 44 %

Procedure:
860 mg piperazine was added to 350 mg 2-chloro-4-ethoxy-pyridine in 3.5 mL n-butanol. The reaction was stirred 1.5 days at 115° C. The reaction was filtered and the filtrate was washed with water and evaporated. 1N HCl was added to the residue and the precpipate was filtered to give 238 mg of the desired product. Rt: 0.3 min (method B), (M+H)+: 208
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:10]2[C:6]([S:7][CH:8]=[CH:9]2)=[CH:5][N:4]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].O>ClCCl>[C:11]([O:1][CH2:2][C:3]1[N:10]2[C:6]([S:7][CH:8]=[CH:9]2)=[CH:5][N:4]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1ncc2sccn12
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCc1ncc2sccn12
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.5 %

Procedure:
To a solution of 0.231 g (1.50 mmol) of the 5-Hydroxymethylimidazo[5,1-b]thiazole prepared in Preparation 10 in 8 ml of dichloromethane was added 0.156 ml (1.65 mmol) of acetic anhydride with ice-cooling, and the mixture was stirred at room temperature for 20 hours. To the reaction solution were added water and a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography using silica gel, eluting with a 30:1 mixture of chloroform and methanol to give 0.237 g (yield 81%) of the title compound.