Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:29]([F:32])([F:31])[F:30])[O:17][N:16]=[C:15]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21](F)=[CH:20][CH:19]=3)[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1>CN(C=O)C>[N:1]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([C:15]2[CH2:14][C:13]([C:8]3[CH:7]=[C:6]([Cl:5])[CH:11]=[C:10]([Cl:12])[CH:9]=3)([C:29]([F:32])([F:30])[F:31])[O:17][N:16]=2)=[CH:19][CH:20]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Sodium azide (3.3 g) is added to a solution of 5-(3,5-dichloro-phenyl)-3-(4-fluoro-naphthalen-1-yl)-5-trifluoromethyl-4,5-dihydro-isoxazole (10.7 g) in DMF (50 ml). After 20 hours at 80° C. another portion of sodium azide is added (3.3 g) and the reaction mixture is stirred for 20 hours at 80° C. The solution is cooled to room temperature and the volume concentrated to 10 ml in vacuo. Water and ethyl acetate are added and the precipitate is collected after filtration to yield 3-(4-azido-naphthalen-1-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole as a beige solid: 183-185° C.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:22])=[CH:4][C:5]2[CH2:6][CH2:7][CH:8]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[CH2:9][C:10]=2[C:11]=1[F:12].[CH:23]#[C:24][CH:25](O)[CH2:26][CH2:27][CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:24]([CH:25]([O:22][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([F:12])[C:2]=1[F:1])[CH2:9][CH:8]([CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]1)[CH2:7][CH2:6]2)[CH2:26][CH2:27][CH3:28])#[CH:23]
Reactant: CCCC1CCC(C2CCc3cc(O)c(F)c(F)c3C2)CC1
Reactant: C#CC(O)CCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C#CC(CCC)Oc1cc2c(c(F)c1F)CC(C1CCC(CCC)CC1)CC2
Reaction time: 19 h

Procedure:
7.0 g (22.7 mmol) of 3,4-difluoro-6-(4-propylcyclohexyl)-5,6,7,8-tetrahydronaphthalen-2-ol are initially introduced in 90 ml of THF together with 2.70 ml (24.0 mmol) of 1-hexyn-3-ol and 6.60 g (25.2 mmol) of triphenylphosphine. 5.3 ml (46.8 mmol) of DIAD in 10 ml of THF are added over the course of 20 min with ice-cooling. After 19 h at RT, water is added, and the mixture is extracted a number of times with MTBE. The combined organic phases are washed with water and saturated sodium chloride soln., and the solution is dried using sodium sulfate. The residue remaining after removal of the solvents is purified by column chromatography (SiO2, n-heptane MTBE=2:1), giving 6-(1-ethynylbutoxy)-7,8-difluoro-2-(4-propylcyclohexyl)-1,2,3,4-tetrahydronaphthalene as a colourless solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].Cl.[N:20]1([C:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:28][N:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(OCC)(=O)C>C(#N)C>[S:28]1[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:26]([N:20]2[CH2:21][CH2:22][N:23]([C:6]([C:5]3[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:4]=3[N:3]([CH2:1][CH3:2])[CH2:17][CH3:18])=[O:8])[CH2:24][CH2:25]2)=[N:27]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nsc3ccccc23)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-diethylamino-5-methanesulfonyl-benzoic acid (Example 2.5) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (CA=87691-88-1) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid. MS (m/e): 473.4 (M+H+; 100%)
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13](O)=[O:14])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O>C1(C)C=CC=CC=1.CN(C)C=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([Cl:21])=[O:14])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(/C=C/C(=O)O)ccc1OC(C)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(/C=C/C(=O)Cl)ccc1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of trans-3-[4-acetyloxy-3-methoxyphenyl]-2-propenoic acid (4 g, 16.93 mmoles) in toluene (70 ml) and dimethylformamide (10 ml) cooled in an ice bath, oxalyl chloride (4.30 g, 33.87 mmoles) is dropped. The mixture is maintained under stirring at 0° C. for 1 hour then the temperature is let reach the room value and it is left for 2 hours. The solvent is removed at reduced pressure and the raw product is used without further purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2(C#N)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C[Mg+].[Br-].CC[O:22][CH2:23][CH3:24].O.Cl>C1(C)C=CC=CC=1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:23](=[O:22])[CH3:24])[CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CCOCC
Reactant: N#CC1(c2ccc(C(F)(F)F)cc2)CCC1
Agent: C[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)C1(c2ccc(C(F)(F)F)cc2)CCC1
Temperature: 95 °C
Yield: 88 %

Procedure:
The starting nitrile, 1-(4-Trifluoromethyl-phenyl)-cyclobutanecarbonitrile, has been described (Parke Davis & Co., U.S. Pat. No. 3,536,656; 1970 and Chemical Abstracts 1970, 73, 109539). To the carbonitrile (2 g) in 5 mL of toluene in a pressure tube was added 10 mL of 3M MeMgBr ether solution (3 equiv.). The tube was sealed and the reaction mixture was heated at 95° C. for 24 hr, cooled to room temperature, poured into 50 mL of water, acidified with 25 mL of 5 M HCl, and this solution was heated at 70° C. for 2 h, cooled, and extracted with ether. The extracts were dried, filtered, concentrated, and purified on silica gel to give pure 1-[1-(4 trifluoromethyl-phenyl)-cyclobutyl]-ethanone (1.9 g, 88%). Data for this ketone: MS 242 (M); 1H NMR (300 MHz, CDCl3) δ 7.6 (d, 8.0 Hz, 2H), 7.4 (d, 8.0 Hz, 2H), 2.75-2.85 (m, 2H), 2.35-2.5 (m, 2H), 1.8-2.0 (3H s and 2H m overlapping); 13C NMR (75 MHz, CDCl3): δ 207.7, 147.5, 129.5, 126.9, 126.1, 125.9 (CF3), 59.5, 30.9, 24.6, 16.1.
Reaction SMILES: [OH-].[Na+].[SH:3][CH2:4][C:5]1([CH2:8][C:9]([O-:11])=[O:10])[CH2:7][CH2:6]1.CO.Cl>O.CC(=O)OCC>[SH:3][CH2:4][C:5]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6]1
Reactant: O=C([O-])CC1(CS)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)CC1(CS)CC1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A 5 L 4-neck round bottle flask was equipped with mechanical stirrer, a thermometer, a condenser, a nitrogen inlet and an additional funnel. Prepare 47% of sodium hydroxide solution from 855 g of sodium hydroxide was dissolved in 972 mL of water. Charge 1800 g of [1-(mercaptomethyl)cyclopropyl]acetate, 1540 mL of methanol to the reaction flask. 1540 g of 47% sodium hydroxide aqueous solution was slowly added to the reaction mixture. After the addition, the reaction mixture was heated to 70˜80° C. and was aged for a period of about 2 hours until completion of reaction as check by TLC (mobile phase: EA/hx=1/2(V/V)). When the reaction was complete, the temperature was lowered below 40° C. The resulting resolution was acidified to pH=3.0˜4.0 with about 1800 mL of 32% HCl aqueous solution. After the reaction mixture was filtered, 2700 g of ethylacetate was added to the filtrate with vigorous stirring over 30 min. The layers were separated; cake and 1000 g of water were added to the aqueous layer and back extracted with 2700 g of ethylacetate. Combined the organic layers and concentrated by rotatory evaporator. Temperature was controlled at 3018 40° C. and pressure was controlled below 100 torr. Distillation was continued to collect about 4000˜5000 mL of distillate. 2000 mL of heptanes was added and the distillation was continued to collect about 1000˜2000 mL at 30˜40° C./<100 torr. After the addition of 2100 g of heptanes, the reaction mixture was cooled to at 10° C. for about 4˜5 hours. A large amount of white solid was obtained by filtration. Cake was washed with 1000 g of heptanes. 1468 g of pure [1-(mercaptomethyl)cyclopropyl]acetic acid was obtained by vacuum dried. (purity by GC: >99%, m.p.=42˜45° C.), H1-NMR(CDCl3): 0.55 ppm (CH2, t), 0.58 ppm (CH2,t), 1.34 ppm (SH, t), 2.50 ppm (CH2, s), 2.60 ppm (CH2, d)
Reaction SMILES: CO.[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH3:13])=[CH:6][C:5]=1[CH2:14][C:15]1[N:19]2[N:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[CH:28]=3)[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1.C=O.[BH3-][C:38]#N.[Na+]>CCOC(C)=O.C(O)(=O)C>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH3:13])=[CH:6][C:5]=1[CH2:14][C:15]1[N:19]2[N:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([CH:29]4[CH2:34][CH2:33][N:32]([CH3:38])[CH2:31][CH2:30]4)[CH:28]=3)[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1
Reactant: [BH3-]C#N
Reactant: Cn1ncc2cc(Cc3cnc4ccc(-c5cnn(C6CCNCC6)c5)nn34)c(F)cc21
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN1CCC(n2cc(-c3ccc4ncc(Cc5cc6cnn(C)c6cc5F)n4n3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To abs. MeOH (2 mL) stirred at rt were added 3-(6-fluoro-1-methyl-1H-indazol-5-ylmethyl)-6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 282, 79 mg, 0.184 mmol), formaldehyde (0.068 mL, 0.918 mmol) and NaBH3CN (58 mg, 0.918 mmol). The RM was then brought to pH 5-6 with addition of acetic acid and stirred at rt for 2 h. It was then taken into EtOAc and washed with saturated NaHCO3 sol. The organic layer was then washed with brine, dried on Na2SO4, filtered and evaporated. The residue was then purified by preparative HPLC with acetonitrile and water (+0.1% TFA) to afford the title compound (tR 0.85 min (conditions 2), MH+=445).
Reaction SMILES: O([C:8]([NH:10][C:11]1[CH:23]=[CH:22][C:14]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1)=[O:9])C1C=CC=CC=1.[NH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C.O>CN(C)C=O>[N:27]1[CH:28]=[CH:29][CH:30]=[C:25]([NH:24][C:8](=[O:9])[NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][CH:23]=2)[CH:26]=1
Reactant: Nc1cccnc1
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)Oc2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(NC(=O)Nc2cccnc2)cc1
Yield: 61.4 %

Procedure:
A solution of ethyl 4-(phenoxycarbonylamino)cinnamate (500 mg), 3-aminopyridine (154 mg) and triethylamine (325 mg) in N,N-dimethylformamide (5 ml) was stirred for 2 hours at 80° C. Water was added thereto, and the resulting precipitate was collected by filtration to give ethyl 4-[3-(3-pyridyl)ureido]cinnamate (307 mg) as a colorless powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([OH:9])=O.N[C@H:11](CC)C(O)=O.N[C@H](CC)C(OC)=O.COC(C1CCCCN1)=O.[Cl:35][C:36]1[N:41]=[C:40](Cl)[C:39]([N+:43]([O-])=O)=[CH:38][N:37]=1>>[Cl:35][C:36]1[N:41]=[CH:40][C:39]2[N:43]([CH3:11])[C:7](=[O:9])[C@H:2]3[CH2:3][CH2:4][CH2:5][CH2:6][N:1]3[C:38]=2[N:37]=1
Reactant: O=C(O)[C@H]1CCCCN1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CC[C@@H](N)C(=O)O
Agent: CC[C@@H](N)C(=O)OC
Agent: COC(=O)C1CCCCN1
Product: CN1C(=O)[C@H]2CCCCN2c2nc(Cl)ncc21

Procedure:
Intermediate D was prepared in the same manner as intermediate B, using (R)-piperidine-2-carboxylic acid as the starting material instead of (R)-2-aminobutanoic acid. No reductive amination step, such as that used for the conversion of compound II to compound III, was required. Rather, methylpiperidine-2-carboxylate was reacted directly with 2,4-dichloro-5-nitropyrimidine in the same manner as is described for the conversion of compound III to intermediate A. 1H NMR (CDCl3) δ: 7.6 (s, 1H), 4.8 (m, 1H), 4.0 (m, 1H), 3.2 (s, 3H), 2.6 (m, 1H), 2.3 (m, 1H), 1.6 (m, 1H), 1.5 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: COc1ccc(C(=O)NC2CCCc3c2[nH]c2ccc(Br)cc32)cc1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methoxybenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and p-anisoyl chloride in a similar manner as described above to give a white solid (11% yield). 1H-NMR (DMSO-de): 810.99 (s, 1H), 8.70 (d, 1H), 7.96 (d, 2H), 7.60 (d, 1H), 7.29 (d, 1H), 7.16 (dd, 1H), 7.02 (d, 2H), 5.38 (m, 1H), 2.67 (m, 2H), 2.08 (m, 2H), 1.87 (m, 2H); MS m/z 399 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH:31]([CH2:35]Cl)[CH2:30]2)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1.[Na+].[Cl-]>C1COCC1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH:31]([CH2:35][C:11]([C:5]3[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13])[CH2:30]2)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1
Reactant: COc1cc(CCN2CCCC(CCl)C2)cc(OC)c1
Reactant: COc1cc(OC)cc(C(C#N)C(C)C)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCN2CCCC(CC(C#N)(c3cc(OC)cc(OC)c3)C(C)C)C2)cc(OC)c1
Temperature: -50 °C
Reaction time: 0.33 h

Procedure:
The reaction mixture is stirred at -50° C. for 20 minutes, a solution of 2.75 g (0.0125 mol) of the nitrile prepared under (a) in 10 cc of THF is then added dropwise, the mixture is stirred again at -50° C. for 30 minutes and a solution of 3 g of the compound prepared under (b) in 10 cc of THF is then added. The reaction mixture is stirred for 1 hour at -50° C. and then left to stand overnight at ambient temperature. It is poured into 0.5 liter of a water/ice mixture, saturated with NaCl and extracted with diethyl ether. The organic phase is dried and evaporated. The oil obtained is chromatographed on a silica 60 column, elution being carried out with a 70/30 CH2Cl2 /acetone mixture.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C@@H:24]3[CH2:29][CH2:28][C@H:27]([N:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)[CH2:26][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.FC(F)(F)C(O)=O.ClCCl.[C:53]([OH:60])(=[O:59])/[CH:54]=[CH:55]\[C:56]([OH:58])=[O:57]>C(OCC)(=O)C>[C:53]([OH:60])(=[O:59])/[CH:54]=[CH:55]\[C:56]([OH:58])=[O:57].[C:53]([OH:60])(=[O:59])/[CH:54]=[CH:55]\[C:56]([OH:58])=[O:57].[C:53]([OH:60])(=[O:59])/[CH:54]=[CH:55]\[C:56]([OH:58])=[O:57].[O:17]([C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([C@H:24]3[CH2:29][CH2:28][C@@H:27]([N:30]4[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]4)[CH2:26][CH2:25]3)[CH:9]=2)=[CH:12][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN([C@H]2CC[C@@H](n3cc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: O=C(O)/C=C\C(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2[C@H]1CC[C@@H](N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The cis-tert-butyl 4-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}-1-piperazinecarboxylate (1.85 g, 3.27 mmol) was treated with a 20% trifluoroacetic acid/dichloromethane solution (60 ml) and stirred for 30 minutes at ambient temperature. The solvents were removed under reduced pressure then the residue was partitioned between dichloromethane (200 ml) and aqueous saturated sodium bicarbonate solution (30 ml). The organic solution was dried over magnesium sulfate, filtered and the filtrate evaporated to a residue (1.55 g). A portion of this material (1.0 g, 2.15 mmol) was dissolved in warm ethyl acetate (220 ml) then treated with maleic acid (0.75 g, 0.44 mmol) in warm ethyl acetate (75 ml). The mixture was cooled to ambient temperature then the solid was collected by filtration and dried to give Cis-5-(4-phenoxyphenyl)-7-(4-piperazinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate salt (1.15 g) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 8.5 (bs, 1H), 8.23 (s, 1H), 7.41-7.51 (m, 5H), 7.08-7.19 (m, 5H), 6.65 (bs, 2H), 6.16 (s, 6H), 4.74 (m, 1H), 1.16-3.2 (m, 17H); RP—HPLC (Hypersil CPS, 5 μm, 100 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 10 min, 1 ml/min) tr=8.63 min; MS: MH+469.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1>O1CCCC1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=3)=[CH:7][CH:6]=2)[C:9](=[O:10])[NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 63.0 mg, 0.20 mmol) in tetrahydrofuran (10 mL) was treated with N,N-diisopropylethylamine (0.082 mL, 0.48 mmol) and nicotinoyl chloride hydrochloride (35.6 mg, 0.20 mmol). The reaction mixture was stirred at 25° C. for 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 ethyl acetate/methanol) afforded N-{4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-phenyl}-nicotinamide (58.9 mg, 70%) as a white solid: mp 240-242° C.; EI-HRMS m/e calcd for C23H24N4O2S (M+) 420.1619, found 420.1625.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=S)[NH2:12])[CH2:7][CH2:6]1)=[O:4].[C:14]([NH2:17])(=[S:16])[CH3:15].II>CO>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:17]=[C:14]([CH3:15])[S:16][N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(N)=S
Reactant: COC(=O)[C@H]1CC[C@H](C(N)=S)CC1
Agent: II
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](c2nsc(C)n2)CC1
Reaction time: 48 h

Procedure:
To a solution of trans-4-thiocarbamoyl-cyclohexanecarboxylic acid methyl ester (0.30 g, 1.5 mmol) and thioacetamide (0.67 g, 8.9 mmol) in methanol (7 ml) was added a solution of iodine (2.65 g, 10.4 mmol) in methanol (15 ml) at room temperature. After stirring for 48 h the reaction mixture was partitioned between 0.1 M sodium thiosulfate solution (100 ml) and ethyl acetate (100 ml). The layers were separated. The aqueous layer was extracted with two 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by Kugelrohr distillation. The distillate was purified by flash-chromatography with n-heptane/tert-butyl methyl ether as eluent to give the title compound (0.021 g, 5%) as light yellow oil, which was contaminated with 20% trans-4-(3-methyl-[1,2,4]thiadiazol-5-yl)-cyclohexanecarboxylic acid methyl ester. MS m/e: 241 ([M+H]+)
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:27])[NH:6][C:7]1[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][OH:26])[CH:18]=2)[N:9]=[C:10]([C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[CH:11]=1.[CH3:30][C@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[C:37]1[N:41]2[CH:42]=[C:43]([O:46][C@H:47]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C@@H:50]([NH2:57])[CH2:49][CH2:48]3)[CH:44]=[CH:45][C:40]2=[N:39][N:38]=1.C[C@H]1CCC[C@@H](C)N1C1N2C=C(O[C@H]3C4C(=CC=CC=4)[C@@H](NC(=O)NC4N(C5C=NN(CCOS(C)(=O)=O)C=5)N=C(C(C)C)C=4)CC3)C=CC2=NN=1>>[C:15]([C:12]([CH3:14])([CH3:13])[C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:57][C@@H:50]2[C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[C@H:47]([O:46][C:43]3[CH:44]=[CH:45][C:40]4[N:41]([C:37]([N:32]5[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]5[CH3:30])=[N:38][N:39]=4)[CH:42]=3)[CH2:48][CH2:49]2)=[O:27])[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][OH:26])[CH:18]=2)[N:9]=1)#[N:16]
Reactant: CC(C)(C#N)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCO)c2)n1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Agent: CC(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5[C@H](C)CCC[C@@H]5C)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C#N)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12

Procedure:
The title compound was prepared using Intermediate 20e and Intermediate 2 in an analogous fashion to the procedure described for Intermediate A step d. LCMS (Method 3): Rt 3.39 min, m/z 690.4 [MH+].
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].[C:12]([OH:21])(=[O:20])[C@@H:13]([C@H:15]([C:17]([OH:19])=[O:18])[OH:16])[OH:14].O>C(O)C.CO>[NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].[CH3:13][OH:14].[C:17]([C@@H:15]([C@H:13]([C:12]([OH:21])=[O:20])[OH:14])[OH:16])([OH:19])=[O:18]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCO
Solvent: O
Solvent: CO
Product: N[C@H]1c2ccccc2C[C@H]1O
Temperature: 60 °C

Procedure:
Racemic cis-1-amino-2-indanol (25.1 g) was dissolved in 375 ml of ethanol. At room temperature a solution of (R,R)-tartaric acid (27.5 g) in 375 ml of methanol was added. The water content was less than 0.1 wt. % relative to methanol. Then the mixture was heated to 60° C. and then cooled down again to 20° C. The solid was recovered by filtration and washed with 100 ml of methanol. After drying, 23.7 g of (1S,2R)-1-amino-2-indanol-(R,R)-tartrate methanol solvate were obtained with an e.e. of 93.1%. D[v, 0.9]=92.7 μm (measured with a Malvern 2600 apparatus).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:29][CH3:30])[C:5]([N:8](COCCO[Si](C)(C)C)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.[N:31]1(C([O-])=O)[CH2:35][CH2:34][CH2:33][CH2:32]1.[H-].[Na+].Cl.CN1CCC[C:44]1=[O:48]>>[ClH:18].[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[C:4]([O:29][CH3:30])=[N:3][C:2]([O:48][CH2:44][C@@H:35]2[CH2:34][CH2:33][CH2:32][NH:31]2)=[CH:7][N:6]=1)(=[O:10])=[O:11]
Reactant: CN1CCCC1=O
Reactant: O=C([O-])N1CCCC1
Reactant: COc1nc(Br)cnc1N(COCCO[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC[C@@H]2CCCN2)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Procedure as for Example 115 using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-({2-[(trimethylsilyl)oxy]ethoxy}methyl)benzenesulphonamide (Example 55a) (0.5 g), tert-butyl (2S)-2-hydroxymethyl)pyrrolidine-1-carboxylate (0.603 g) and sodium hydride (0.12 g of a 60% dispersion in oil) in N-methylpyrrolidinone (20 mL). The adduct was deprotected with HCl (4M in dioxane) to afford the titled adduct (0.241 g) as a white solid.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC(OC)OC.[CH2:21](O)[CH2:22][OH:23]>>[CH:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]32[O:23][CH2:22][CH2:21][O:13]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCCO
Reactant: O=C1CCCCC1C1CCCCC1
Solvent: COC(OC)OC
Product: C1CCC(C2CCCCC23OCCO3)CC1

Procedure:
1,260 g (7 mols) of 2-cyclohexyl-cyclohexanone are reacted with 816.2 g (7.7 mols) of trimethylorthoformate and 477.4 g (7.7 mols) of anhydrous 1,2-ethanediol in a manner analogous to that in Example 1.