Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]2[NH:17][CH:16]=[N:15][N:14]=2)[O:4]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26]>CC(C)=O>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]2[N:17]=[CH:16][N:15]([CH2:25][CH3:26])[N:14]=2)[O:4]1
Reactant: CO[C@@H]1O[C@H](c2nnc[nH]2)[C@H]2OC(C)(C)O[C@@H]12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1cnc([C@H]2O[C@@H](OC)[C@@H]3OC(C)(C)O[C@@H]32)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A solution of 3-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4H-1,2,4-triazole (Preparation 20) (1.0 g, 4.2 mmol), potassium carbonate (0.57 g, 4.2 mmol) and iodoethane (0.33 ml, 4.2 mmol) in acetone (10 ml) was heated under reflux for one hour. Further iodoethane (0.05 ml, 0.6 mmol) and potassium carbonate (0.1 g, 0.7 mmol) were added and heating under reflux continued for 30 minutes. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane gradually changing to dichloromethane:methanol (97:3 by volume) to give the title compound (0.4 g) (TLC data—Rf 0.65 in solvent system dichloromethane:methanol 95:5 by volume).
Reaction SMILES: CS([C:5]1[N:6]=[C:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:8]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10][C:9]=2[N:25]=1)(=O)=O.[CH3:37][O-:38].[Na+]>CO.CC(O)=O>[CH3:37][O:38][C:5]1[N:6]=[C:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:8]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10][C:9]=2[N:25]=1
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Yield: 90.5 %

Procedure:
A solution of [2-methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine (Example 53; 44 mg, 0.08 mmol) and NaOMe (100 mg, 0.25 mmol) in MeOH (1.5 mL) was heated at 60° C. for 1 h. The mixture was cooled, acidified with HOAc (3 drops), and directly purified using Preparative HPLC (conditions as in Example 54) to give the title compound (35 mg, 89%). MS (ESI): mass calcd. for C22H19F6N5O, 483.15; m/z found, 484.8 [M+H]+. 1H NMR (CDCl3): 9.63 (s, 1H), 8.39 (d, J=3.3 Hz, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.73 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.06-7.02 (m, 1H), 3.88 (s, 3H), 3.50-3.44 (m, 4H), 3.26-3.22 (m, 2H), 3.11-3.07 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][CH:11]2[CH2:13][C:12]2([F:15])[F:14])=[CH:7][C:5]([NH2:6])=[C:4]([F:16])[CH:3]=1.N([O-])=O.[Na+].[NH:21]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:22]1[C:23](O)=[O:24].C([N:32](CC)CC)C>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[C:8]([O:9][CH2:10][CH:11]2[CH2:13][C:12]2([F:14])[F:15])=[CH:7][C:5]([N:6]2[C:23]([O-:24])=[C:22]3[CH2:26][CH2:27][CH2:28][CH2:29][N+:21]3=[N:32]2)=[C:4]([F:16])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)C1CCCCN1
Reactant: Nc1cc(OCC2CC2(F)F)c(Cl)cc1F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: [O-]c1c2[n+](nn1-c1cc(OCC3CC3(F)F)c(Cl)cc1F)CCCC2
Temperature: -10 °C

Procedure:
4.6 g 4-Chloro-5-(2,2-difluorocyclopropylmethoxy)-2-fluoroaniline was suspended in a mixture of 9.7 ml concentrated sulphuric acid and 41.5 ml water and cooled to -10° C. A solution of 1.38 g sodium nitrite in 4.2 ml water was added dropwise at such a rate that the temperature of the reaction mixture did not rise above -5° C. After the addition it was stirred for a further hour at -5° C. and excess nitrous acid destroyed with urea until a test with iodine-starch paper was negative. The solution thus obtained was warmed to 0° C. and added dropwise to an ice-cold solution of 2.3 g pipecolic acid and 8.3 ml triethylamine in 27.7 ml water. After the addition it was stirred for a further hour at 0° C. and the reaction mixture extracted several times with methylene chloride. The organic phases were combined, dried over magnesium sulphate and the solvent evaporated. The residue was taken up in 40 ml ether and treated with 4.14 ml acetic anhydride and 2.07 ml pyridine. The mixture was stirred overnight at room temperature, then poured into ice-water and extracted with ethyl acetate. The organic phases were dried over magnesium sulphate and the solvent evaporated. The residue was chromatographed on silica gel using 95 parts ethyl acetate and 5 parts methanol as eluent.
Reaction SMILES: ClC1C=C(Cl)C=CC=1N1N=C(C(O)=O)C2C3CCC(C4C3=CC=CC=4)C1=2.[CH:27]12[CH2:39][CH2:38][CH:34]([C:35](=[O:37])[CH2:36]1)[C:33]1[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=1.C[Si](C)(C)N[Si](C)(C)C.[Li]CCCC.[C:54](OCC)(=[O:60])[C:55]([O:57][CH2:58][CH3:59])=[O:56]>>[O:60]=[C:54]([CH:36]1[C:35](=[O:37])[CH:34]2[CH2:38][CH2:39][CH:27]1[C:28]1[C:33]2=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:55]([O:57][CH2:58][CH3:59])=[O:56]
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C1CC2CCC1c1ccccc12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(O)c1nn(-c2ccc(Cl)cc2Cl)c2c1C1CCC2c2ccccc21
Agent: [Li]CCCC
Product: CCOC(=O)C(=O)C1C(=O)C2CCC1c1ccccc12

Procedure:
The title product was prepared by a procedure similar to that described for step 1 of intermediate 1. From tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-one [prepared by one of the methods available in the art of organic synthesis, e.g., as described in Hales et. al. Tetrahedron, 1995, 51, 7777-7790] (2.5 g, 14.53 mmol), hexamethyldisilazane (4.9 ml, 23.2 mmol), 2.34M n-BuLi (10 ml, 23.4 mmol) and diethyl oxalate (3.18 ml, 21.18 mmol) the desired product was obtained (2.3 g, 63%).
Reaction SMILES: [OH:1][CH:2]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1)[CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:20])([F:19])[CH:16]([F:18])[F:17])[CH:9]=1)C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:53]([CH2:56]C)CC)C.[OH2:58]>O1CCCC1>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[O:27][C:24]1[CH:23]=[CH:22][C:21]([CH:2]2[O:1][C:56](=[O:58])[NH:53][CH:3]2[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:20])([F:19])[CH:16]([F:17])[F:18])[CH:9]=2)=[CH:26][CH:25]=1
Reactant: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccn2)cc1
Reactant: CCN(CC)CC
Reactant: O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(Cc2cccc(OC(F)(F)C(F)F)c2)C(c2ccc(Oc3ccccn3)cc2)O1

Procedure:
To a solution of (2RS,3RS)-3-hydroxy-3-[4-(pyridin-2-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoic acid (4.49 g, 9.65 mmol, crude) in tetrahydrofuran (60 ml) were added diphenylphosphoryl azide (2.29 ml, 10.6 mmol) and triethylamine (2.02 mmol, 14.5 mmol), and the mixture was heated under reflux for 2 hrs. The reaction solution was allowed to cool and water (100 ml) was added. The mixture was extracted with ethyl acetate (100 ml×2). The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1). Recrystallization from ethyl acetate-hexane gave the objective substance (3.56 g, 80%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1O)[CH:5]=[O:6].[C:11](=[O:14])([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21]Br>CC(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:14][CH2:11][C:23]1[CH:20]=[CH:19][C:18]([Cl:17])=[C:25]([Cl:26])[CH:24]=1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc(CBr)cc1Cl
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccc(Cl)c(Cl)c2)c(OCc2ccc(Cl)c(Cl)c2)c1
Yield: 84.1 %

Procedure:
To a solution of 2 g of 3,4-dihydroxybenzaldehyde in 40 ml of acetone, were added 4.40 g of anhydrous potassium carbonate and 6.24 g of 3,4-dichlorobenzyl bromide. The mixture was refluxed for 24 hours. The reaction mixture was then removed of the acetone by distillation under reduced pressure, admixed with 200 ml of water, and the intended product was extracted with 200 ml of chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and stripped of the chloroform by distillation under reduced pressure to precipitate white crystals. The raw crystals were recrystallized from ethyl alcohol to give 4.99 g of colorless crystals having a melting point of 181°-183° C. The IR absorption spectrum of the compound, as measured in KBr-tablet, showed the following absorption maxima (in wave number, cm-1) 658, 693, 710, 760, 795, 805, 830, 875, 1030, 1135, 1168, 1200, 1245, 1280, 1370, 1403, 1437, 1460, 1470, 1510, 1585, 1600, 1690, 2730, 2830, 2870, 2910, and 3070.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5]([CH3:12])([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:22][Si:23]([CH2:26][CH2:27][O:28][CH2:29]Cl)([CH3:25])[CH3:24]>ClCCl>[CH3:12][C:5]1([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3][CH:2]([O:1][CH2:29][O:28][CH2:27][CH2:26][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH2:7][CH2:6]1
Reactant: COC(=O)C1(C)CCC(O)CC1
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(C)CCC(OCOCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of methyl 4-hydroxy-1-methylcyclohexane-1-carboxylate (2.1 g, 12.19 mmol, 1.00 equiv) in 20 mL of dichloromethane was added DIEA (4.74 g, 36.68 mmol, 3.01 equiv) and SEMCl (4.08 g, 24.47 mmol, 2.00 equiv) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature and quenched with water. The resulting solution was extracted with 3×100 mL of ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/20) to give the desired methyl 1-methyl-4-[[2-(trimethylsilyl)ethoxy]methoxy]cyclohexane-1-carboxylate (3.6 g, 98%) as a colorless oil.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH:20]=[O:21])[CH:12]=1)=O)(C)(C)C.[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[CH:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][C@@H:9]([C:22]([O:24][CH3:25])=[O:23])[NH2:8])=[CH:12]1)=[O:21]
Reactant: COC(=O)[C@H](Cc1cn(C=O)c2ccccc12)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1cn(C=O)c2ccccc12
Reaction time: 15 h
Yield: 99 %

Procedure:
To methylene chloride (200 mL) solution of the compound obtained in Example 28 (8.9 g, 25.7 mmol) was added dropwise 4 mol/L of hydrogen chloride-dioxane (19 mL) at room temperature, and the mixture was allowed to stir for 15 hours. The crystals precipitated were filtered, and washed with diethyl ether, to give the captioned compound (7.2 g, 99%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:16]=[C:17]([O:24][CH3:25])[C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=O>>[Br:14][C:15]1[CH:16]=[C:17]([O:24][CH3:25])[C:18]([OH:23])=[C:19]([CH:22]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: COc1cc(Br)cc(C=O)c1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: COc1cc(Br)cc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1O

Procedure:
6-[4-(5-Bromo-2-hydroxy-3-methoxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-bromo-2-hydroxy-3-methoxybenzaldehyde. Mass spectrum (ES) MH+=395.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[CH:3][CH:2]=1.[CH:21]([Mg]Cl)=[CH2:22].[ClH:25]>C1COCC1>[Cl:25][CH2:21][CH:22]=[C:7]([C:4]1[CH:5]=[CH:6][C:1]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:2][CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cl
Reactant: C=C[Mg]Cl
Reactant: O=C(c1ccccc1)c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClCC=C(c1ccccc1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 29 %

Procedure:
A mixture of ((1,1′-biphenyl)-4-yl)phenylmethanone (0.01 mol) in THF (200 ml) was stirred at room temperature under N2 flow. Vinylmagnesium chloride (0.011 mol; 1M solution in THF) was added dropwise. The mixture was stirred at room temperature for 1 hour. HCl (150 ml) was added. The mixture was stirred at room temperature for 1 hour and extracted with DIPE. The organic layer was separated, washed once with a saturated K2CO3 solution, twice with H2O and once with a saturated NaCl solution, then dried, filtered and the solvent was evaporated. This fraction was purified by column chromatography over silica gel (eluent: CH2Cl2hexane/EtOAc 50/30/20). Two pure fractions were collected and their solvents were evaporated, yielding 8.8 g (29%) of 4-(3-chloro-1-phenyl-1-propenyl)(1,1′-biphenyl) (interm. 22).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C1CCCCC=1>C(O)C.[Pd].CCOCC>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: COc1ccccc1C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Solvent: C1=CCCCC1
Product: COc1ccccc1C1CCNCC1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of 1-benzyloxycarbonyl-4-(2-methoxyphenyl)piperidine (0.67 g) in ethanol (10 mL) was treated with cyclohexene (4.2 mL) followed by 10% palladium on carbon (0.13 g). After heating to reflux for 2 hours, the reaction mixture was cooled to room temperature, diluted with ether and extracted with 1N hydrochloric acid. The aqueous layer was made basic with sodium bicarbonate and extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulfate and evaporated to afford the piperidine (0.2 g); NMR (CDCl3): 1.60 (d of q, 2, J1 =12, J2 =4), 1.73-1.82 (broad, 2), 2.74-2.83 (d of t, 2, J1 =12, J2 =2), 3.02-3.2 (m, 3), 3.82 (s, 3), 6.85 (d, 1, J=8), 6.9 (m, 1), 7.15-7.26 (m, 2); MS: m/z=192(M+1). This material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[NH:11][C:12](=[S:22])[CH2:13][N:14]=1
Reactant: CCc1cc2c(s1)NC(=O)CN=C2c1ccccc1Cl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CCc1cc2c(s1)NC(=S)CN=C2c1ccccc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 136 %

Procedure:
[a] To a solution of 40 g of 5-o-chlorophenyl-7-ethyl-1,2-dihydro-3H-thieno[2,3-e][1,4]diazepin-2-one in 200 ml of pyridine is added 32 g of phosphorus pentasulfide, and the mixture is stirred at 60°C for 1 hour. After allowing to cool, the reaction mixture is poured into 2 liters of ice water with stirring. The precipitate formed is collected with suction filtration and washed with water. The precipitate is dissolved in chloroform, and the solution is washed with a saturated sodium bicarbonate and washed with water. The chloroform layer is dried over sodium sulfate and concentrated in vacuo. The residue is recrystallized from a mixture of ethanol and chloroform to give 31.4 g of 5-o-chlorophenyl-7-ethyl-1,2-dihydro-3H-thieno[2,3-e][1,4]diazepine-2-thione as yellowish crystals melting at 198°-199°C (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](OC)[CH:11]=1)[N:8]=[C:7]([Cl:14])[N:6]=[CH:5]2.NC1C=CC(Br)=C([F:25])C=1C#N>>[Br:1][C:2]1[C:3]([F:25])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:14])[N:6]=[CH:5]2
Reactant: COc1cc(Br)cc2cnc(Cl)nc12
Reactant: N#Cc1c(N)ccc(Br)c1F
Product: Fc1c(Br)ccc2nc(Cl)ncc12

Procedure:
6-bromo-2-chloro-5-fluoro-quinazoline is prepared analogously to WO 2007/117607 or to the above-mentioned synthesis of 6-bromo-2-chloro-8-methoxy-quinazoline starting from 2-amino-5-bromo-6-fluoro-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][CH2:11][CH2:12]O)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.S(Cl)([Cl:19])=O>ClC(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][CH2:11][CH2:12][Cl:19])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NCCCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NCCCCl
Reaction time: 4 h

Procedure:
To a stirred mixture of 10 parts of 3-[(4,5-dichloro-2-nitrophenyl)amino]-1-propanol and 75 parts of trichloromethane are added dropwise 11.2 parts of sulfinyl chloride. Upon completion, stirring is continued for 4 hours at reflux temperature. The reaction mixture is evaporated and the residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 4,5-dichloro-N-(3-chloropropyl)-2-nitrobenzenamine; mp 78° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11]2[N:12]=[C:13]([N:16]=[C:17]([NH2:19])[NH2:18])[S:14][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CS[C:22](SC)=[N:23][C:24]#[N:25].[CH3:28][NH2:29]>CN(C)C=O>[NH2:18][C:17]([NH2:19])=[N:16][C:13]1[S:14][CH:15]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([CH2:2][NH:1][C:22]([NH:29][CH3:28])=[N:23][C:24]#[N:25])[CH:4]=2)[N:12]=1
Reactant: CN
Reactant: COc1ccc(-c2csc(N=C(N)N)n2)cc1CN
Reactant: CSC(=NC#N)SC
Solvent: CN(C)C=O
Product: CNC(=NC#N)NCc1cc(-c2csc(N=C(N)N)n2)ccc1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4-(3-aminomethyl-4-methoxyphenyl)-2(diaminomethyleneamino)thiazole (350 mg) and N-[di(methylthio)methylene]cyanamide (190 mg) in N,N-dimethylformamide (20 ml) was heated at 70° C. for 2.5 hours. After cooling, 40% methylamine solution (6 ml) was added to the mixture and the mixture was stirred for 5 hours at room temperature. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (10:1). Recrystallization from a mixture of methanol and diisopropyl ether afforded 2-(diamino-methyleneamino)-4-[3-{(3-methyl-2-cyanoguanidino)methyl}-4-methoxyphenyl]thiazole (180 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12](O)=[O:13])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[NH3:21].[CH3:22]O>>[CH3:22][NH:21][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[N+:18]([O-:20])=[O:19])[CH:10]=1
Reactant: N
Reactant: Cc1ccc(Sc2cccc(C(=O)O)c2)c([N+](=O)[O-])c1
Reactant: CO
Product: CNC(=O)c1cccc(Sc2ccc(C)cc2[N+](=O)[O-])c1
Yield: 96 %

Procedure:
The product from Example 86a (0.25 g, 0.86 mmol) was reacted as described in Example 84c substituting N-methyl amine in methanol for ammonia to give the title compound (0.25 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[CH:8](=O)[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11]>>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[OH:11])=[N:5][N:6]=1
Reactant: O=Cc1ccccc1O
Reactant: Cc1nnc(C)s1
Product: Cc1nnc(C=Cc2ccccc2O)s1
Temperature: 150 °C
Reaction time: 30 h

Procedure:
570 g (5 moles) of 2,5-dimethyl-1,3,4-thiadiazole and 275 g (2.5 moles) of salicylaldehyde are mixed and the mixture is slowly heated to 150° C. whilst passing nitrogen through it. The mixture is kept at 150° C. for 30 hours and is then cooled, the excess 2,5-dimethyl-1,3,4-thiadiazole is distilled off and the residue is recrystallized from methylglycol. 304 g (56% of theory) of yellow crystals of melting point 253°-254° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:18])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14].CC(C)([O-])C.[Na+].[CH3:36][C@H:37]1[C@H:41]([CH3:42])OS(=O)(=O)[O:38]1.Cl>CN(C)C(=O)C>[OH:38][C@@H:37]([CH3:36])[C@H:41]([N:5]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:14])[F:15])=[C:2]([CH3:1])[C:3]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:18])=[CH:4]1)[CH3:42]
Reactant: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c[nH]c1-c1ccccc1C(F)(F)F
Reactant: C[C@@H]1OS(=O)(=O)O[C@H]1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cn([C@H](C)[C@H](C)O)c1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a solution of 4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (28 g, 66 mmol) in anhydrous N,N-dimethylacetamide (DMA) (0.53 L) was added sodium tert-butoxide (15 g, 15 mmol) and stirred at room temperature for 30 min under N2. (4S,5S)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide (15 g, 99 mmol) in anhydrous DMA (2.0 ml) was added to the solution and stirred at 70° C. for 2.0 h. The reaction mixture was cooled to room temperature and added 2N HCl (0.14 L) and concentrated on a rotary evaporator. To this residue was added anhydrous tetrahydrofuran (THF) (140 ml) and 5N HCl (0.14 L) and stirred at 60° C. for 90 min. The mixture was diluted with ethyl acetate and washed with water, saturated NaHCO3 and brine, then dried over sodium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by silica-gel column chromatography (9:1 to 1:1 dichloromethane:ethyl acetate) to give an atropisomeric mixture of title compound as a white solid (22.5 g, 69%).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.Br[C:19]1C=C2C(C=CN2)=C[CH:20]=1.[Li]C(C)(C)C.CN1CCC(=O)CC1>>[OH:1][C:2]1([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)[CH2:7][CH:6]2[N:5]([CH2:8][CH2:19][CH2:20]2)[CH2:4][CH2:3]1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CN1CCC(O)(c2ccc3cc[nH]c3c2)CC1
Agent: CN1CCC(=O)CC1
Agent: [Li]C(C)(C)C
Product: OC1(c2ccc3cc[nH]c3c2)CCN2CCCC2C1

Procedure:
In a similar fashion, 6-[4-Hydroxy-1-methyl-piperidin-4-yl]-indole was prepared from 6-bromoindole (1.0 g, 5 mmol); KH (0.225 g, 5.6 mmol), 1.7M tBuLi (7.5 ml, 12.7 mmol) and N-methyl-4-piperidone (1.246 g, 10.9 mmol). Yield 0.382 g (35%).