Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26].C(OC([NH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=O)(C)(C)C.O.Cl>C(OCC)(=O)C>[NH2:43][CH:44]1[CH2:49][CH2:48][N:47]([C:16]2[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]3[C:8](=[O:26])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=4)[CH2:14][CH2:13][CH2:12][O:11][C:10]=3[N:15]=2)[CH2:46][CH2:45]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C1c2c(-c3ccccc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: NC1CCN(c2cc(-c3ccccc3)c3c(n2)OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Temperature: 140 °C
Reaction time: 5 h
Yield: 77.9 %

Procedure:
A mixture of 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (40.0 mg) and 4-(t-butoxycarbonylamino)piperidine (38.9 mg) was stirred at 140° C. for 5 hours. To the remaining product, water was added and the mixture was extracted with ethyl acetate, followed by drying on anhydrous sodium sulfate. The solvent was then removed to obtain a residue. To this residue, a 3 mol/L ethyl acetate solution of hydrogen chloride (1 mL) was added and the mixture was stirred at room temperature for 1 hour. The solvent was again removed to obtain a residue. To this residue, ethyl acetate was added and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate, followed by drying on anhydrous sodium sulfate. The solvent was then removed and the resulting residue was purified on a silica gel column chromatography (ethyl acetate:methanol=3:1) to obtain 9-(4-aminopiperidine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (35.0 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8]([C:10]2C(C3C=CC=C([N+]([O-])=O)C=3)C(C(OC(C)C)=O)=C(C)[NH:14][C:15]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1.C(O)C>C(O)(C)C>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8](=[O:9])/[CH:10]=[C:15](\[NH2:14])/[CH3:16])=[CH:4][CH:3]=1
Reactant: CC1=C(C(=O)OCc2ccc(Cl)cc2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Solvent: CC(C)O
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccc(Cl)cc1
Yield: 78 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid isopropyl ester and 75 mmols of β-aminocrotonic acid 4-chlorobenzyl ester in 120 ml of isopropanol gave 2,6-dimethyl-3-isopropoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 4-chlorobenzyl ester of melting point 137° C (from ethanol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.[OH-].[Ca+2:13].[OH-].C(#N)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O>[Ca+2:13].[CH2:22]([O:21][C:19]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O-:11])=[O:10])[CH2:3][CH2:2]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:22]([O:21][C:19]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O-:11])=[O:10])[CH2:3][CH2:2]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)CCC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C([O-])CCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
3-(4-Piperidyl)propionic acid (20.0 g, 0.12 mol) and calcium hydroxide (14.1 g, 0.19 mol) were suspended in 47 g water and 195 g acetonitrile at 15-25° C. and then cooled to 0-10° C. Benzyl chloroformate (23.9 g, 0.14 mol) was added within 30 minutes and the reaction stirred at 0-5° C. for 2 h. The product precipitated during the reaction and was isolated by filtration to afford the title compound in 95% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:21][CH2:20][C:15]4(OCCO4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:28]([O:32][C:33]([N:35]1C2C(CNCC2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH:15]2[CH:14]([CH2:13][N:12]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:21][CH2:20]2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC2CNCCC21
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC4(CC3)OCCO4)cc2n1
Product: CC(C)(C)OC(=O)N1CCC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CCC21

Procedure:
Prepared according to the method used in the preparation of 8-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane using octahydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester in place of 1,4-dioxa-8-aza-spiro[4.5]decane. The title compound was obtained as white solid (153 mg, 90%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.CC1COCCN1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH:23]2[CH3:28])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC1COCCN1
Product: CC1COCCN1c1nc(C(C)(C)C)nc2c1nnn2Cc1ccccc1Cl

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-methylmorpholine and isolated as light-yellow gum (12.7 mg, 67%). MS (m/e): 401.5 (MH+).
Reaction SMILES: C1C2C(COC(N[C@@H](CSC[C@H](O)CO)C(OC(C)(C)C)=O)=O)C3C(=CC=CC=3)C=2C=CC=1.C(Cl)(=O)CCCCCCC.[C:44]([O:57][CH2:58][C@@H:59]([O:89][C:90](=[O:102])[CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97]CCCC)[CH2:60][S:61][CH2:62][C@H:63]([NH:71][C:72]([O:74][CH2:75][CH:76]1[C:88]2[CH:87]=[CH:86][CH:85]=[CH:84][C:83]=2[C:82]2[C:77]1=[CH:78][CH:79]=[CH:80][CH:81]=2)=[O:73])[C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])(=[O:56])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]CCCC>>[C:44]([O:57][CH2:58][C@@H:59]([O:89][C:90](=[O:102])[CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH3:97])[CH2:60][S:61][CH2:62][C@H:63]([NH:71][C:72]([O:74][CH2:75][CH:76]1[C:88]2[CH:87]=[CH:86][CH:85]=[CH:84][C:83]=2[C:82]2[C:77]1=[CH:78][CH:79]=[CH:80][CH:81]=2)=[O:73])[C:64]([O:66][C:67]([CH3:68])([CH3:70])[CH3:69])=[O:65])(=[O:56])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCC
Agent: CC(C)(C)OC(=O)[C@H](CSC[C@H](O)CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCCCCCCC(=O)Cl
Product: CCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OC(=O)CCCCCCC

Procedure:
The product was prepared from (R)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-((R)-2,3-dihydroxypropylthio)propanoate (10, 1 eq) and octanoyl chloride (3.7 eq) by following the procedure described for compound 11.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[BrH:12].BrBr>C(O)(=O)C>[BrH:12].[Br:12][CH:3]1[C:2](=[O:1])[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4]1
Reactant: O=C1CCCc2cccnc21
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C1c2ncccc2CCC1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.68 g of 8-oxo-5,6,7,8-tetrahydroquinoline in 25 ml of acetic acid, 2.5 ml of a 25% solution of hydrobromic acid in acetic acid was added, followed by the dropwise addition of 0.235 ml of bromine. After stirring at room temperature for 30 minutes, the solvent was evaporated. The resulting residue was washed with diethyl ether, whereby 1.5 g of 7-bromo-8-oxo-5,6,7,8-tetrahydroquinoline hydrobromide was obtained.
Reaction SMILES: [OH-].[Li+].C1COCC1.[CH3:8][N:9]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([O:17]C)=[O:16])=[N:10]1.Cl>O>[CH3:8][N:9]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=[O:16])=[N:10]1
Reactant: COC(=O)c1nn(C)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn(C)nc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Lithium hydroxide (0.864 g), THF (30 ml) and water (30 ml) were added to methyl 1,4-dimethyl-1H-pyrazole-3-carboxylate (1.39 g) and the reaction was stirred at room temperature for 3 h. The reaction was acidified with 5M HCl (aq) to pH to 7 and then washed through a waters HLB OASIS cation exchange cartridge. The cartridge was preconditioned with methanol, then water. The reaction was loaded onto the cartridge and washed with water, then eluted with methanol. The methanol fraction was evaporated in vacuo to give title compound, 1.1 g.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)#[CH:25]>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]2[N:3]=[N:2][N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[CH:25]=2)=[CH:27][CH:28]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1cc(-c3ccc(F)cc3)nn1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 1-ethynyl-4-fluorobenzene. MS (+ESI) m/z: 391.1.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH:30]2[CH2:39][CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31]2)(=O)=O)=CC=1>>[CH2:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:38][CH2:39][CH:30]1[CH2:29][N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccccc3C2)cc1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Product: O=C(N[C@H]1CCN(CC2CCc3ccccc3C2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide and (1,2,3,4-tetrahydronaphthalen-2-yl)methyl p-toluenesulfonate were reacted under the same conditions as in Example 6 to give (S)-N-(1-((1,2,3,4-tetrahydronaphthalen-2-yl)methyl)pyrrolidin-3-yl)-1-adamantanecarboxamide.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:39])[CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][N:33]=2)[CH:27]=1)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][N:33]=4)[CH:27]=3)[CH2:24][C:23](=[O:39])[NH:16][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncn2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccncn3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (128 mg, 0.5 mmol) and 3-oxo-3-(3-pyrimidin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K43) (179 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (115 mg).
Reaction SMILES: [CH2:1]([N:3]([CH3:17])[C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:2].[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:1]([N:3]([CH3:17])[C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH3:18])[C:12]([CH3:13])([CH3:15])[CH3:14])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCN(C)C(=O)c1ccccc1NC(C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCN(C)C(=O)c1ccccc1N(C)C(C)(C)C
Temperature: 40 °C
Yield: 95.6 %

Procedure:
A mixture of N-ethyl-N-methyl 2-(N-tert-butylamino)benzamide (1.89 g, 8.1 mmol), potassium carbonate (2.2 g, 15.9 mmol), and methyl iodide (2.3 g, 16.2 mmol) in DMF (40 mL) was heated overnight at 40° C., then was partitioned between EtOAc and water. The EtOAc was dried (MgSO4), concentrated, and purified by HPLC with 1:4 ethyl acetate/cyclohexane to afford 1.923 g of N-ethyl-N-methyl 2-(N-methyl-N-tert-butylamino)benzamide as a yellow oil, a 96% yield.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:20]=[CH:19][C:10]([CH:11]=[C:12]3[S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][OH:32]>CN(C=O)C>[F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:20]=[CH:19][C:10](/[CH:11]=[C:12]3/[C:13](=[O:18])[N:14]([CH2:30][CH2:31][OH:32])[C:15](=[O:17])[S:16]/3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(Oc3ccc(F)cc3)cc2)S1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1S/C(=C\c2ccc(Oc3ccc(F)cc3)cc2)C(=O)N1CCO
Temperature: 0 °C

Procedure:
To a solution of 5-(4-(4-fluorophenoxy)benzylidene)thiazolidine-2,4-dione (0.05 g) in a 1:1 mixture of ThF and DMF (1.6 mL) was added anhydrous K2CO3 (0.022 g). To the well stirred homogeneous mixture was added 2-chloro-ethanol (0.04 g) and stirred ovemight at room temperature. The reaction was diluted with ice-water, extracted with EtOAc, and the organic layer was washed with water, dried (Na2SO4) and concentrated in vacuo to give the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[CH:11](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cnn(C(c2ccccc2)c2ccccc2)c1
Temperature: 100 °C

Procedure:
A suspension of 1H-pyrazole-4-carboxylic acid ethyl ester (1.0 g), benzhydryl chloride (1.9 ml) and potassium carbonate (1.48 g) in anhydrous 1-methyl-2-pyrrolidinone (10 ml) was heated at 100° C. under nitrogen for 6 h. It was diluted with water and extracted with ethyl acetate, the organic extracts washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with i-hexane/ethyl acetate (4:1) followed by i-hexane/ethyl acetate (2:1) to give the sub-title compound (2.18 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[C:4]([N+:13]([O-])=O)[CH:3]=1.[H][H]>[Ni].C(O)C>[NH2:13][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NCCCO
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(Cl)ccc1NCCCO

Procedure:
A mixture of 34.6 parts of 3-[(4-chloro-2-nitrophenyl)amino]-1-propanol and 320 parts of ethanol is hydrogenated at normal pressure and at room temperature with 8 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 30 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol as an oily residue.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([O:16][CH2:17]C)=[O:15])=[C:12](S(C)(=O)=O)[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:23][O:24][Na]>CO>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([O:24][CH3:23])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CO[Na]
Reactant: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1S(C)(=O)=O
Solvent: CO
Product: CCc1ccc(-c2nsc(OC)c2C(=O)OC)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of ethyl 3-(4-ethylphenyl)-5-methanesulfonyl-1,2-thiazole-4-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), methanol (15 mL), MeONa (119.47 mg, 5.00 equiv). The resulting solution was stirred for 2 h at 70° C. in an oil bath. The resulting solution was extracted with 2×15 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×30 mL of brine, dried over anhydrous Na2SO4. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 141.4 mg (crude) of methyl 3-(4-ethylphenyl)-5-methoxy-1,2-thiazole-4-carboxylate as white oil. Mass spectrum (ESI, m/z): Calcd. for C15H17NO3S, 292.1 (M+H). found 292.1.
Reaction SMILES: [C:1]1(P)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:8]([Cl:13])(Cl)(Cl)(Cl)[Cl:9]>C1(C)C=CC=CC=1>[C:1]1([P:8]([Cl:13])[Cl:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Pc1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: ClP(Cl)c1ccccc1
Temperature: 70 °C

Procedure:
38.5 g (0.34 mol) phenylphosphine dissolved in 40 ml toluene was added at 25° C. to a suspension of 160 g PCl5 (0.77 mol) in 500 ml toluene. After the exothermal reaction had subsided, the whole was heated to 70° C. until gas ceased to be evolved. The low boilers were removed under vacuum. The crude product yield was 67 g; 31P-NMR: δ P=161 ppm, C6H5PCl2, 94.4 mol%. The residue was distilled under vacuum. bp 98° C./17 mbar; yield: 50.6 g (81% of the theoretical).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[CH:4][N:3]=1.[K+].[CH:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([NH-:31])(=[O:30])=[O:29])=[N:26][CH:27]=1)([CH3:21])[CH3:20]>CN(C=O)C>[CH:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([NH:31][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[CH:4][N:3]=2)(=[O:30])=[O:29])=[N:26][CH:27]=1)([CH3:21])[CH3:20]
Reactant: COc1ccccc1Oc1c(Cl)ncnc1Cl
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(Cl)ncnc1NS(=O)(=O)c1ccc(C(C)C)cn1
Yield: 64.4 %

Procedure:
A solution of 2.71 g of 4,6-dichloro-5-(o-methoxyphenoxy)-pyrimidine (Example 10b) and 5.0 g of 5-isopropyl pyridine-2-sulfonamide potassium salt (Example 1e) in 50 ml of DMF was stirred at room temperature for 20 h. The solvent was removed in vacuo, the residue was taken up in 200 ml of 10% aqueous acetic acid and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The crude product was crysallised from a mixture of 2-propanol and diethyl ether. The crystals were collected, washed with cold 2-propanol and diethyl ether and dried to give 2.8 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide as white crystals. LC-MS: tR=4.99 min, [M+1]+=435.25, [M−1]−=433.28.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10](OCC)(=O)[C:11](OCC)=O.CC(C)([O-])C.[K+]>CN(C=O)C.O>[CH2:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:11]
Reactant: CCOC(=O)C(=O)OCC
Reactant: c1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ccc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of indole product in Example 38 (150 mg, 0.572 mmol) and diethyl oxalate (92 mg, 0.63 mmol) in DMF (5 mL), potassium tert-butoxide (71 mg, 0.63 mmol) was added in one portion at room temperature under nitrogen. The reaction mixture was warmed to reflux under nitrogen for 1 h and then was cooled down to room temperature. The mixture was diluted with water (50 mL) and extracted (3×) with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, EtOAc/hexanes, 1:1) to afford the N-ethyl-indole, Example 38, (144 mg, 86%): 1H NMR (500 MHz, CDCl3) δ 7.18-7.28 (m, 5H), 7.09 (d, J=3.2 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.42 (dd, J=3.2, <1 Hz, 1H), 4.36 (t, J=8.0, 5.4 Hz, 1H), 4.12 (q, J=7.3 Hz, 2H), 4.00 (d, J=15.1 Hz, 1H), 3.85 (d, J=15.1 Hz, 1H), 3.07 (dd, J=11.3, 5.4 Hz, 1H), 2.66 (dd, J=11.3, 8.0 Hz, 1H), 2.50 (s, 3H), 1.44 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[C:5]([O:17][CH3:18])[CH:4]=1)=[O:2].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:15]=[CH:16][C:3]([CH:1]=[O:2])=[CH:4][C:5]=1[O:17][CH3:18])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C=O)ccc1OCCCCCCO
Solvent: c1ccncc1
Product: COc1cc(C=O)ccc1OCCCCCCOC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
A flame-dried, 250 mL round bottom flask was charged, under argon, with 2 (10 g, 39.6 mmol) and this was dissolved in 50 mL of anhydrous pyridine and the flask was protected from light. To this solution was added acetic anhydride (9.3 mL, 98.8 mmol) dropwise at a rate of 0.5 mL/minute. The solution was stirred at room temperature for 30 minutes at which time all of the starting material had been consumed. The solvent was evaporated with reduced pressure and then toluene was added to remove excess pyridine. Evaporation of the solvent in vacuo gave 11.5 g (99%) of 3 as an off-white solid. Rf=0.74 (33% ethyl acetate/hexane). Mp 74.0-75.0° C. 1H NMR (400 MHz, DMSO-d6): δ9.83 (s, 1), 7.53 (dd, J=1.6 Hz, 8.4 Hz, 1), 7.39 (d, J=2.0 Hz, 1),), 7.17 (d, J=8.4 Hz, 1), 4.07 (t, J=6.4 Hz, 2), 4.00 (pt, J=6.4 Hz, 6.8 Hz, 2), 3.83 (s, 3), 2.00 (s, 3) 1.74 (m, 2), 1.58 (m, 2), 1.4-1.35 (m, 4) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2.C1(C)C=CC=CC=1>C(O)(=O)C>[F:14][C:13]([F:15])([F:16])[C:10]([CH:11]=[N:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2)([OH:17])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:20][CH3:21])([CH3:18])[CH3:19]
Reactant: Nc1cccc2[nH]ncc12
Reactant: COc1ccc(Br)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(Br)cc1C(C)(C)CC(O)(C=Nc1cccc2[nH]ncc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 96 h
Yield: 89.5 %

Procedure:
300 mg (0.813 mmol) of 4-(5-bromo-2-methoxyphenyl)-2hydroxy-4-methyl-2-(trifluoromethyl)pentanal is mixed in 1.19 ml of glacial acetic acid with 108.2 mg (0.813 mmol) of 4-aminoindazole, and it is stirred for four days at room temperature. The batch is spun in until a dry state is reached, and the residue is drawn off three times with toluene. Chromatography on silica gel (mobile solvent:ethyl acetate/hexane) yields 352.5 mg (89.5%) of the desired imine (together with the imine of the Desbrom compound).